From DEPAZ@vm1.sdi.uam.es Tue Jan 10 05:36:38 1995 Received: from vm1.sdi.uam.es for DEPAZ@vm1.sdi.uam.es by www.ccl.net (8.6.9/930601.1506) id FAA21918; Tue, 10 Jan 1995 05:32:52 -0500 Message-Id: <199501101032.FAA21918@www.ccl.net> Received: from vm1.sdi.uam.es by vm1.sdi.uam.es (IBM VM SMTP V2R2) with BSMTP id 1004; Tue, 10 Jan 95 11:30:36 HOE Received: from vm1.sdi.uam.es (DEPAZ) by vm1.sdi.uam.es (Mailer R2.08) with BSMTP id 2430; Tue, 10 Jan 95 11:30:35 HOE Date: Tue, 10 Jan 95 11:27:27 HOE From: "Dr. Jose Luis Garcia de Paz" Organization: Native address: Subject: Convert cartesian coordinates to inertia axis coord syste To: Computational Chemistry List Dear CCL'ers, I am using G92/DFT. Cartesian coordinates are given wiht charge center in origin. I will like to convert it to the system with origin in the center of masses and using as axis the momentum of inertia axis. Is there any share program to do it?. Thank you very much and Have a Happy New Year 1995. Regards Jose Dr. Jose Luis Garcia de Paz (34) (1) 3974957. FAX (34) (1) 3974512. Departamento de Quimica Fisica Aplicada. FACULTAD DE CIENCIAS, C-XIV-602. Universidad Autonoma de MAdrid. 28049-Madrid (Spain). From desmond@om3.ch.umist.ac.uk Tue Jan 10 06:35:25 1995 Received: from nessie.mcc.ac.uk for desmond@om3.ch.umist.ac.uk by www.ccl.net (8.6.9/930601.1506) id GAA00508; Tue, 10 Jan 1995 06:33:50 -0500 Received: from om3.ch.umist.ac.uk (actually trigger.ch.umist.ac.uk) by nessie.mcc.ac.uk with SMTP (PP); Tue, 10 Jan 1995 11:33:34 +0000 Received: by om3.ch.umist.ac.uk (940406.SGI/) for chemistry%ccl.net@nessie.mcc.ac.uk id AA08593; Tue, 10 Jan 95 11:45:01 GMT Date: Tue, 10 Jan 1995 11:44:59 +0000 (GMT) From: Simon Collins Subject: Bond orders To: chemistry@ccl.net Message-Id: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII Dear all When calculating bond orders on the SPARTAN package you are presented with results from Lowdin and Mulliken analysis. Is one of these models generally accepted to be better than the other or are there advantages and disadvantages to both methods. I would greatly appreciate any information, references etc anyone has on this subject. Cheers ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Simon Collins - Dept. Chemistry, UMIST, Manchester. M60 1QD Tel: 061-236-3311 x4476 Fax: 061-236-7677 E-mail: desmond@trigger.ch.umist.ac.uk S.Collins@umist.ac.uk ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ From mbasd@dl.ac.uk Tue Jan 10 09:39:34 1995 Received: from mserv1.dl.ac.uk for mbasd@dl.ac.uk by www.ccl.net (8.6.9/930601.1506) id IAA23191; Tue, 10 Jan 1995 08:45:59 -0500 Received: from s-crim1.dl.ac.uk by mserv1.dl.ac.uk with SMTP id NAA12390 (8.6.9/5.3[ref pg@dl.ac.uk] for dl.ac.uk from mbasd@dl.ac.uk); Tue, 10 Jan 1995 13:45:04 GMT Precedence: first-class Received: by s-crim1.dl.ac.uk (931110.SGI/930817.MJE) for chemistry@ccl.net id AA00122; Tue, 10 Jan 95 13:45:01 GMT Date: Tue, 10 Jan 95 13:45:01 GMT From: mbasd@seqnet.dl.ac.uk Message-Id: <9501101345.AA00122@s-crim1.dl.ac.uk> To: chemistry@ccl.net Subject: Oral availability of drugs... Dear Readers, I would be grateful for comments, ideas, anecdotes, references etc. on the following topic: In the area of drug research, a frequent problem which arises is that of obtaining oral-availability: it is usually more desirable to have an orally active compound than one which is active only when injected. What I want to know is the following: 1 Is it possible to predict whether a compound will be orally active? 2 On observing a compound has little or no oral activity, are there any structural modifications which can be used to increase the oral activity of the compound? 3 Is it possible to use an adjuvant to increase the absorption of a weakly orally active compound? 4 Are there any in vitro test systems which will predict whether a compound is orally active? If there are such test systems, are they available commercially or have they been devloped in-house? I will summarise useful information to the net. Andy Sheppard Ferring Research Institute mbasd@seqnet.dl.ac.uk [crossposted to newsgroups bionet.general, bionet.molbio.methds-reagnts, bionet.molec-model and the Computational Chemistry list] From nauss@ucmod2.che.uc.EDU Tue Jan 10 10:35:31 1995 Received: from ROCK.SAN.UC.EDU for nauss@ucmod2.che.uc.EDU by www.ccl.net (8.6.9/930601.1506) id JAA24327; Tue, 10 Jan 1995 09:55:22 -0500 Received: from ucmod2.che.uc.edu by UCBEH.SAN.UC.EDU (PMDF V4.3-10 #7238) id <01HLOE2FMDF4HSMQZQ@UCBEH.SAN.UC.EDU>; Tue, 10 Jan 1995 09:51:58 -0500 (EST) Received: by ucmod2.che.uc.edu (920330.SGI/920502.SGI.AUTO) for @uc.edu:CHEMISTRY@ccl.net id AA27816; Tue, 10 Jan 95 09:56:18 -0500 Date: Tue, 10 Jan 1995 09:56:18 -0500 From: nauss@ucmod2.che.uc.EDU (Jeffrey L. Nauss) Subject: CCL: AMBER parameters for Ba2+ and Sr2+ To: CHEMISTRY@ccl.net Reply-to: nauss@ucmod2.che.uc.EDU Message-id: <9501101456.AA27816@ucmod2.che.uc.edu> Content-transfer-encoding: 7BIT Would anyone happen to have AMBER parameters for the ions Ba2+ and Sr2+? The actual parameters and/or references would be most appreciated. Thank you. Jeff Nauss **************************************************************************** * UU UU Jeffrey L. Nauss, PhD * * UU UU Director, Molecular Modeling Services * * UU UU Department of Chemistry * * UU UU CCCCCCC University of Cincinnati * * UU UU CCCCCCCC Cincinnati, OH 45221-0172 * * UUUU CC * * CC Telephone: 513-556-0148 Fax: 513-556-9239 * * CC * * CCCCCCCC e-mail: nauss@ucmod2.che.uc.edu * * CCCCCCC * **************************************************************************** From MMADRID@CPWSCA.PSC.EDU Tue Jan 10 10:47:56 1995 Received: from CPWSCA.PSC.EDU for MMADRID@CPWSCA.PSC.EDU by www.ccl.net (8.6.9/930601.1506) id KAA26859; Tue, 10 Jan 1995 10:15:28 -0500 Date: Tue, 10 Jan 1995 10:15:44 -0500 (EST) From: MMADRID@B.PSC.EDU To: chemistry@ccl.net Message-Id: <950110101544.2040533c@B.PSC.EDU> Subject: CCL: Pittsburgh Supercomputing Center offering NMR workshop STRUCTURE DETERMINATION USING NMR Pittsburgh Supercomputing Center June 25-28, 1995 Pittsburgh Supercomputing Center (PSC) is offering biomedical researchers a "Structure Determination Using NMR" Workshop. The objective is to introduce participants to the different techniques for the elucidation of solution structures of biological macromolecules from nuclear magnetic resonance data. The workshop is free to academic participants. Topics will include: The worskhop will consist of lectures and extensive hands-on sessions. The programs AMBER, Mardigras and MidasPlus will be discussed. Hands-on sessions will be emphasized. Participants will be able to work on the examples provided or on their own experimental data. No prior supercomputing experience is necessary. Workshop leaders are: Dr. David Case, The Scripps Research Institute; Dr. Thomas James, University of California, San Francisco; Dr. Julie Newdoll, Computer Graphis Laboratory, University of California, San Francisco; and Dr. Uli Schmitz, University of California, San Francisco. This workshop is funded by a grant from the Biomedical Research Technology Program, National Center for Research Resources, National Institutes of Health. Travel, meals and hotel accommodations for researchers affilated with U.S. academic institutions are supported by this grant. Enrollment is limited to 20. An application form is included. Deadline for applications is: April 28, 1995. * * * * * * * * * * PITTSBURGH SUPERCOMPUTING CENTER BIOMEDICAL INITIATIVE STRUCTURE DETERMINATION USING NMR June 25-28, 1995 APPLICATION Name:________________________________________________________________________ Affiliation:_________________________________________________________________ Address:_____________________________________________________________________ (Business) _____________________________________________________________________________ ____________________________________________________________________________ (Home) ____________________________________________________________________________ Telephone: ____________________ ______________________ (Business) (Home) *Social Security Number: _______-_____-_______ Citizenship: ____________ Electronic Mail Address:____________________________________________________ Status: ___Graduate ___Post-doctoral Fellow ___Faculty ___Other (specify) Please indicate specifically any special housing, transportation or dietary arrangements you will need: _______________________________________________ How did you learn about this workshop? _____________________________________ REQUIREMENTS: Applicants must submit a completed application form and a cover letter. The letter should describe, in one or two paragraphs, your current research and how participating in the workshop will enhance this research. Please include a brief statement describing your level of experience with computers. Faculty members, staff and post-docs should provide a curriculum vita. Graduate students must have a letter of recommendation from a faculty member. Please return all application materials by APRIL 28, 1995 to: Biomedical Workshop Applications Committee Pittsburgh Supercomputing Center 4400 Fifth Avenue, Suite 230C Pittsburgh, PA 15213 Direct inquiries to: Nancy Blankenstein, blankens@psc.edu or 412/268-4960. *Disclosure of Social Security Number is voluntary. PSC does not discriminate on the basis of race, color, religion, sex, age, creed, national or ethnic origin, or handicap. From gedeck@pctc.chemie.uni-erlangen.de Tue Jan 10 10:59:34 1995 Received: from faui45.informatik.uni-erlangen.de for gedeck@pctc.chemie.uni-erlangen.de by www.ccl.net (8.6.9/930601.1506) id JAA28462; Tue, 10 Jan 1995 09:39:33 -0500 Received: from faui43.informatik.uni-erlangen.de by uni-erlangen.de with SMTP; id AA26205 (5.65c-6/7.3w-FAU); Tue, 10 Jan 1995 13:42:47 +0100 Received: from pctc.chemie.uni-erlangen.de by immd4.informatik.uni-erlangen.de with SMTP; id AA20317 (5.65c-6/7.3m-FAU); Tue, 10 Jan 1995 13:42:43 +0100 Received: from pc1.chemie.uni-erlangen.de by pctc.chemie.uni-erlangen.de (AIX 3.2/UCB 5.64/4.03) id AA15815; Tue, 10 Jan 1995 13:42:31 +0100 Received: by pc1.chemie.uni-erlangen.de (AIX 3.2/UCB 5.64/4.03) id AA14774; Tue, 10 Jan 1995 13:42:24 +0100 Date: Tue, 10 Jan 1995 13:42:20 +0100 (NFT) From: Peter Gedeck To: CHEMISTRY@ccl.net Cc: Peter Freunscht , czernek@chemi.muni.cz, jabs@cis.biochemtech.uni-halle.de Subject: Summary - Scaling of vibrational frequencies Message-Id: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII I received a lot of responses for the following question: >this time I would like to ask, why vibrational frequencies are usually >scaled by a factor (0.89-0.9)? > >As far as I know, this is independent of the calculational method used >(ab-initio or semiempirical). So, is it a deficiency of the theoretical >approach or is it just a question of the accuracy of the calculation? Thanks a lot to all who replied, Peter Gedeck ============================================================ Summary - Scaling of vibrational frequencies: ------------------------------------------------------------ Suggested literature: o J. A. Pople, R. Krishnan, H. B. Schlegel, D. DeFrees, J. S. Binkley, M. J. Frisch, R. F. Whiteside, R. F. Hout and W. J. Hehre, Int. J. Quantum Chem., Quantum Chem. Symposium, 15 (1981) 269. o MP2 scaling D. J. DeFrees, J Comp Chem 82 (1985) 333. o B.H. Besler, et.al., J. Chem. Phys. 89(1) (1988) 360. o Possible sources of error in empirical scaling... C. L. Janssen and H. F. Schaefer, J Chem Phys 95 (1991) 5128. o J.F. Stanton, et.al., J. Chem. Phys. 94(1) (1991) 404. o M. Flock and M. Ramek, Int J. Quantum Chem., Quantum Chem. Symposium 27 (1993) 331-341. o There is also a recent (ca. 1993) paper by Pople et al in Israel J Chem on scaling MP2 freqs. o A. P. Scott et.al. Israel J. Chem. 33 (1993) 345. o Ab Initio Molecular Orbital Theory - by Hehre, Radom, Schleyer and Pople. (Wiley, New York, 1986) Possible reasons for the deficiency of simple HF-calculations: Vibrational frequencies are usually calculated from the normal mode frequencies using a harmonic osciallator model - Zero point energy - Anharmonicity in the vibrational potential energy surface - Basis sets are too small - neglect of electron correlation - the Hartree-Fock potential is too steep and therefore frequencies too high. ============================================================ Following are all responses (edited): ------------------------------------------------------------ From: Dave Young The answer is that all of these frequencies are being computed with a harmonic oscilator approximation. For high frequency modes, the difference between the harmonic oscilator prediction and the exact or Morse potential like behavior is about 10% . If you try to look at very low frequency modes, below a few hundred wave numbers, you will see that the frequencies calculated are off by a large amount. ------------------------------------------------------------ From: "David W. Ewing (216) 397-4241" There are three sources of error in the calculation of vibrational frequencies via ab initio methods: calculated frequencies are usually harmonic, basis sets are too samll, and electron correlation is neglected or inadequately treated. For discussions of the last two factors, see B.H. Besler, et.al., J. Chem. Phys. 89(1), 360 (1988). J.F. Stanton, et.al., J. Chem. Phys. 94(1), 404 (1991). ------------------------------------------------------------ From: Anthony P Scott The scaling of calculated harmonic vibrational frequencies to match the experimentally determined (anharmonic) vibrational frequencies is designed to allow for the harmonic approximation that is used in the theoretically determined values. Our paper, Israel J. Chem. 1993, 33, 345 is a good place to start when exploring this. ------------------------------------------------------------ From: Doug Fox The vibrational frequencies predicted by ab initio and semi empirical methods are almost all harmonic approximations and limited in some respect by the dissociation behaviour of the underlying method. The first approximation tends to produce values higher than experimental due to the lack of anharmonic corrections. The improper dissociation behaviour also tends toward high estimates because most SCF based methods tend not to dissociate and single configuration representations tend to be worse away from equilibrium. The remarkable result of the above facts is that for a wide range of molecules studied at the HF level a scaling of 0.89 or about about 12% brings the frequencies into good agreement with experiment. Much better than attempting to correct the problem with high order correlation treatments. A different scaling should be used for MP2 or higher order corrected methods but as you noted often this is not done. There is a good bit of discussion of the results in "Ab Initio Molecular Orbital Theory" by Hehre, Radom, Schleyer and Pople. There are some recent papers which are revisiting this issue. Aue and co-workers have told me they have one in press using MP2 results. ------------------------------------------------------------ From: "E. Lewars" The general belief seems to be that it's because the calculations (which use the eigenvalues of a force constant matrix) assume the vibrations are harmonic. However, it has been claimed that "this straightfoward looking consideration is wrong..."; see M. Flock and M. Ramek, Int J. Quantum Chem., Quantum Chem. Symposium 27, 331-341 (1993). Some other refs to vib freq scaling are Possible sources of error in empirical scaling... C. L. Janssen and H. F. Schaefer, J Chem Phys 1991 95 5128. MP2 scaling D. J. DeFrees, J Comp Chem 1985 82 333. There is also a recent (ca. 1993) paper by Pople et al in Israel J Chem on scaling MP2 freqs. ------------------------------------------------------------ From: Per-Ola Norrby It's a little of both. If you look at earlier postings to this list, you can see that the correction factors are different for different levels of theory, so low level calculations are certainly slightly deficient in the description of the energy hypersurface. However, vibrational frequencies are usually calculated from the Hessian with no consideration of higher derivatives. This gives an harmonic approximation, resulting in a slightly to "hard" system and too high calculated frequencies. Naturally, having one scaling factor for all frequencies at one level of theory is an oversimplification, but I don't know of anyone who tried anything more complicated. If you do, it might not be "ab initio" anymore... ------------------------------------------------------------ From: Csonka Gabor The IR scaling factor IS method dependent. The 0.9 is for HF. For MP2 you should use different scaling. For DFT or CCSD(T) you usually get the correct harmonic frequencies within an error bar, so no scaling is necessary. The scaling is mainly for the zero point energy, and it may give wrong results for individual freqs. I refer to Hehre et al.: ad Initio MO Theory book (Wiley, 1986) and the work P. Pulay and G. Fogarasy ------------------------------------------------------------ From: Adel El-Azhary The ab initio frequencies calculated at the Hartree Fock level are usually overestimated by about 10-20%. This is due to the incompletness of the basis set used, neglect of anharmonicity and neglect of the electron correlation. Frequencies calculated at the MP2 level of theory are overestimated by about 5-10%. This is due to inclusion of the electron correlation at the second level but higher excitations in the wave funcation are also neglected. You can look at the JPC, 1987, there is a paper by R. Amos about furan, pyrrole and thiophene. These is also a paper accepted for publication very recently by Petr Bour in the JPC where frequencies were calculated at the HF, MP2 and MP2 anharmonic also. This is in addition to the other references mentioned in the e-mail you received through the CCL. ------------------------------------------------------------ From: Janet Del Bene <@vm.gmd.de:FR042008@YSUB.BITNET> Ab initio calculations of vibrational frequencies at the Hartree-Fock level are too high compared to experimental frequencies. The scaling (0.89) is an empirical adjustment that brings the computed frequencies into better agreement with the experimental. That computed Hartree-Fock frequencies are too high is a result of two factors: 1) the computed frequencies are based on a parabolic potential and are harmonic, whereas the experimental frequencies are anharmonic; 2) the Hartree-Fock potential is too steep and as a result, frequencies are too high. ------------------------------------------------------------ From: @uunet.uu.net:aefrisch@m10.UUCP (AEleen Frisch) The reference for the HF frequency scale factor is: J. A. Pople, R. Krishnan, H. B. Schlegel, D. DeFrees, J. S. Binkley, M. J. Frisch, R. F. Whiteside, R. F. Hout and W. J. Hehre, Int. J. Quantum Chem., Quantum Chem. Symposium, 15, 269 (1981). Scaling is done to account for well-known, systematic errors in Hartree-Fock frequencies due to its neglect of electron correlation. ------------------------------------------------------------ From: Kui Zhang The fellowing paper and book will answer your question: J.A. Pople et al, Ab Initio Molecular Orbital Theory (Wiley, New York, 1986). H.F. Schaefer III et al, J. Chem. Phys. 95, 5128 (1991). ------------------------------------------------------------ From: Eric Bittner The scaling looks like a fudge factor to compensate for zero point energy and anharmonicity in the vibrational potential energy surface. In most structure calculations, the vbrational frequencies are just the normal mode frequencies...i.e harmonic classical motion. ------------------------------------------------------------ From: Patrick Bultinck Well, you can't really call it a deficiency in the calculation, but there is a deficiency in the model used for the vibrations... it's the harmonic approximation. This way you get frequencies that are too big, and that's why we use a 0.89 scaling factor. Intensities are even worse, they use the double harmonic approximations... I think about every book on advanced QC will give some insight (Daudel e.g., Pople et al. "Ab Initio MO theory...) ------------------------------------------------------------ From: Earl EVLETH p 74208 The scaling factor 0.89 came from HF 6-31G* level calculations. Larger basis sets might change that scaling and MP2 level calculations at the 6-31G* will change it into the 0.95 or 0.96 range. However, Pulay showed years ago when he did his modeling of various structures, scaling factor depends on the type of vibration one is dealing with, i.e. bond stretching, bond bending, and torsional modes. He scaled force constants, not the final vibrational frequencies. Therefore, the 0.89 magic number is just a convenient, practically off-the-top-of-one's-head factor useable for HF 6-31G* calculations. The computed low energy torsional modes are largely fiction and scaling or not scaling them is a technical detail. As for nearly pure bending and stretching (little coupling) these might be pretty good. Some people find that good old semiempirical calculations gives good unscaled results! ------------------------------------------------------------ Peter Gedeck Inst. f. Physikalische Chemie I Egerlandstrasse 3 91058 Erlangen Germany Tel: ++9131 - 85 7335 Fax: ++9131 - 85 8307 E-Mail: gedeck@pctc.chemie.uni-erlangen.de WWW: http://pctc.chemie.uni-erlangen.de/~gedeck/gedeck.html From ravishan@swan.wcc.wesleyan.edu Tue Jan 10 11:36:01 1995 Received: from swan.wcc.wesleyan.edu for ravishan@swan.wcc.wesleyan.edu by www.ccl.net (8.6.9/930601.1506) id KAA09452; Tue, 10 Jan 1995 10:44:53 -0500 Received: by swan.wcc.wesleyan.edu (AIX 3.2/UCB 5.64/4.03) id AA11766; Tue, 10 Jan 1995 10:48:21 -0500 Date: Tue, 10 Jan 1995 10:48:21 -0500 Message-Id: <9501101548.AA11766@swan.wcc.wesleyan.edu> From: "G. Ravishanker" To: chemistry@ccl.net Subject: UV Wavelength & Computer monitors Hi I am posting this on behalf of a colleague of mine. He is interested in knowing the frequency of UV radiation emanating from computer monitors. Specifically, whether it falls in which of the following category: UVA - 320-400 nm UVB - 290-320 nm UVC - <290 nm Any help is appreciated. Ravi -- **************************************************************************** * Ganesan Ravishanker Ph: (203) 685-2104 * * Coordinator of Scientific Computing, Fax:(203) 685-2211 * * Adjunct Associate Professor(Dept. of Chem.) * * Wesleyan University e-mail:ravishan@swan.wcc.wesleyan.edu * * Middletown, CT 06459. * **************************************************************************** From sunger@crl.com Tue Jan 10 12:36:49 1995 Received: from mail.crl.com for sunger@crl.com by www.ccl.net (8.6.9/930601.1506) id LAA22824; Tue, 10 Jan 1995 11:39:33 -0500 Received: from crl5.crl.com by mail.crl.com with SMTP id AA08707 (5.65c/IDA-1.5 for ); Tue, 10 Jan 1995 08:38:49 -0800 Received: by crl5.crl.com id AA10866 (5.65c/IDA-1.5); Tue, 10 Jan 1995 08:38:52 -0800 Date: Tue, 10 Jan 1995 08:38:51 -0800 (PST) From: Stefan Unger To: mbasd@s-crim1.dl.ac.uk Cc: chemistry@ccl.net Subject: Re: CCL:Oral availability of drugs... In-Reply-To: <9501101345.AA00122@s-crim1.dl.ac.uk> Message-Id: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII On Tue, 10 Jan 1995 mbasd@s-crim1.dl.ac.uk wrote: > What I want to know is the following: > > 1 Is it possible to predict whether a compound will be orally active? Oral activity is dependent upon many factors: dosage formulation and route (pill, gavage, liquid ...), inherent solubility, microcrystalline state, species, metabolism, etc. > 2 On observing a compound has little or no oral activity, are there any > structural modifications which can be used to increase the oral activity > of the compound? It would depend on the reason for lack of activity. See 4. You could try to block metabolic deactivation, improve solubility, improve formulation, etc. > 3 Is it possible to use an adjuvant to increase the absorption of a > weakly orally active compound? Yes, liposome formulation, for example. Various microcrystalline forms may have different solubilities, etc. > 4 Are there any in vitro test systems which will predict whether a > compound is orally active? If there are such test systems, are they > available commercially or have they been devloped in-house? You can get software to predict solubility and lipophilicity, and also metabolism. Empirically, most CNS active agents (and most "typical" drugs) seem to have an octanol/aqueous partition coefficient of logP = 2 (approx). But this depends upon class, e.g. penicillins are much more hydrophilic. A good strategy might be to try to approximate the phys-chem properties of known structurally related orally active compounds (solubility and log P (oct). Hope this helps. Contact me off-line for informaiton on software. > I will summarise useful information to the net. > > Andy Sheppard > Ferring Research Institute > mbasd@seqnet.dl.ac.uk > > [crossposted to newsgroups bionet.general, bionet.molbio.methds-reagnts, > bionet.molec-model and the Computational Chemistry list] > > > -------This is added Automatically by the Software-------- > -- Original Sender Envelope Address: mbasd@dl.ac.uk > -- Original Sender From: Address: mbasd@seqnet.dl.ac.uk > CHEMISTRY@ccl.net -- everyone | CHEMISTRY-REQUEST@ccl.net -- coordinator > MAILSERV@ccl.net: HELP CHEMISTRY | Gopher: www.ccl.net 73 > Anon. ftp www.ccl.net | CHEMISTRY-SEARCH@ccl.net -- archive search > http://www.ccl.net/chemistry.html | for info send: HELP SEARCH to MAILSERV > > From husuter@cscs.ch Tue Jan 10 13:35:41 1995 Received: from pobox.cscs.ch for husuter@cscs.ch by www.ccl.net (8.6.9/930601.1506) id MAA19240; Tue, 10 Jan 1995 12:38:57 -0500 Received: from viglio.cscs.ch by pobox.cscs.ch with SMTP inbound id <10363-0@pobox.cscs.ch>; Tue, 10 Jan 1995 18:38:43 +0100 From: husuter Message-Id: <9501101740.AA27967@viglio.cscs.ch> Received: by viglio.cscs.ch id AA27967; Tue, 10 Jan 95 18:40:23 +0100 Subject: G92-Question/POP-Output To: CHEMISTRY@ccl.net Date: Tue, 10 Jan 95 18:40:22 MET X-Mailer: ELM [version 2.3 PL11] Dear Netters, does anyone know how to convince, the Gaussian Program to printout the selected points and the values at these points (of the electrostatic potential) for the CHELP and Merz-Kollman procedures? thanks for your help H.U. Suter, CSCS, 6928 Manno, Switzerland From ellen@nautilus.ariad.com Tue Jan 10 13:46:41 1995 Received: from ariad.com for ellen@nautilus.ariad.com by www.ccl.net (8.6.9/930601.1506) id NAA10291; Tue, 10 Jan 1995 13:12:53 -0500 Received: from nautilus.ariad.com by ariad.com (4.1/4.1-NEARnet) id AA14133; Tue, 10 Jan 95 13:13:54 EST Received: by nautilus.ariad.com (931110.SGI/930416.SGI) for @ariad.ariad.com:chemistry@ccl.net id AA20852; Tue, 10 Jan 95 13:13:28 -0500 From: ellen@nautilus.ariad.com (Ellen R. Laird) Message-Id: <9501101813.AA20852@nautilus.ariad.com> Subject: Kd vs IC50 To: chemistry@ccl.net Date: Tue, 10 Jan 95 13:13:28 EST Reply-To: Organization: ARIAD Pharmaceuticals, Inc. X-Mailer: ELM [version 2.3 PL11] Greetings: It is well known that for two compounds competing for binding to the same protein with equilibrium dissociation constants Kd_1 and Kd_2, the difference in the Gibbs free energy of binding is given by ddG(2-1) = -RT ln(Kd_2/Kd_1) It is common in the pharmaceutical industry to have assays that generate IC50 values rather than equilibrium constants. Clearly, if the ratio IC50_2/IC50_1 = Kd_2/Kd_1 then the IC50 ratio may be used in the above equation. I am requesting opinions and references on the following: If this ratio equivalence has not been demonstrated (i.e., K_n have not been measured in a comparable assay), is there a general relationship that can be drawn between IC50 and Kd? I have read a straightforward treatment of this *for enzymes* by Cheng and Prusoff (Biochemical Pharmacology, 1973, 22, 3099 - thanks to Dr. James Blake of Pfizer Central Research for supplying this reference); according to their analysis, Kd for an inhibitor is equal to the IC50 only when noncompetitive or uncompetitive kinetics apply. Their analysis assumes simple Michaelis-Menten behavior, and begins from that equation: V_max [S] V_0 = ------- K_m + [S] i.e., rates of catalysis are involved in the derivation Unfortunately, I am dealing with binding to non-catalytic protein domains; it is not clear to me how one could extend the Cheng and Prusoff arguments to compounds that simply inhibit receptor-ligand interactions. On a related issue - it is evident from the literature that the majority of researchers in medicinal chemistry use a direct comparison of IC50 values as sufficient for determining the relative efficacy among a set of inhibitors; other than a desire to validate ddG computed by via sophisticated simulations, do computational chemists involved in pharmaceutical research even care to consider IC50 data in terms of free energy relationships? I'll post a summary of responses, and thanks in advance - Ellen ------------------------------------------------------------------------------- ~~~~~~ ~~~~~~~~ Ellen R. Laird ~~~~~~~~~~ ellen@ariad.com ~~~~~~~~~~ ~~~~~~~~ ~~~~~~ARIAD Pharmaceuticals, Inc. 26 Landsdowne St. Cambridge MA 02139 (617) 494-0400, ext 234 fax: 494-8144 ------------------------------------------------------------------------------- From holbrook@CAMIS.Stanford.EDU Tue Jan 10 14:36:32 1995 Received: from CAMIS.Stanford.EDU for holbrook@CAMIS.Stanford.EDU by www.ccl.net (8.6.9/930601.1506) id OAA24784; Tue, 10 Jan 1995 14:28:01 -0500 Received: (holbrook@localhost) by CAMIS.Stanford.EDU (8.6.8.1/8.6.5) id LAA00784 for chemistry@ccl.net; Tue, 10 Jan 1995 11:28:00 -0800 Date: Tue, 10 Jan 95 11:28:00 PST From: Robin Holbrook To: chemistry@ccl.net Subject: NMR Course Announcement Message-ID: International School of Biological Magnetic Resonance, 2nd Course: "Dynamics & the Problem of Recognition in Biological Macromolecules" May 19-30, 1995 Ettore Majorana Centre for Scientific Culture, Erice, Sicily, Italy An advanced graduate course devoted to the analysis of the dynamic behavior of biological macromolecules by nuclear magnetic resonance. 10 days of lectures, workshops and tutorials w/~20 lecturers - attendance limited to ~75 students. Sponsored by FEBS, NATO and the sponsors of the Ettore Majorana Centre. Registration including full room and board during course: $1,000 US. Some partial scholarships available. For information and/or registration contact either: holbrook@camis.stanford.edu (Ms. Robin Holbrook, Course Administrative Assistant) or the Directors: Dr. Oleg Jardetzky (Email: jardetzky@camis.stanford.edu Fax: 415/723-2253) or Dr. Jean-Francois Lefevre (Email: lefevre@bali.u-strasbg.fr Fax: +33/88 65 53 43) From rmuller@invitro.usc.edu Tue Jan 10 15:35:47 1995 Received: from usc.edu for rmuller@invitro.usc.edu by www.ccl.net (8.6.9/930601.1506) id OAA27211; Tue, 10 Jan 1995 14:52:20 -0500 Received: from invitro.usc.edu by usc.edu (4.1/SMI-3.0DEV3-USC+3.1) id AA29361; Tue, 10 Jan 95 10:51:18 PST Received: by invitro.usc.edu (AIX 3.2/UCB 5.64/SMI-4.1+ucs-3.6) id AA27787; Tue, 10 Jan 1995 10:51:18 -0800 Date: Tue, 10 Jan 1995 10:51:18 -0800 From: rmuller@invitro.usc.edu (Richard P. Muller) Message-Id: <9501101851.AA27787@invitro.usc.edu> To: CHEMISTRY@ccl.net Subject: QMC Electronic Structure Reply-To: rmuller@invitro.usc.edu (Richard P. Muller) I'm writing in search of review articles on the state of the art in Quantum Monte Carlo calculations on the electronic structure of molecules. I'm particularly interested in those reviews that compare the QMC results to Hartree-Fock+Correlation (i.e. CI, CC, MPn, etc) methods. Please email directly to me, and I'll summarize back to the CCL list when I have all of the responses. Thanks in advance... Rick Muller rmuller@invitro.usc.edu From MMADRID@B.PSC.EDU Tue Jan 10 16:02:41 1995 Received: from B.PSC.EDU for MMADRID@B.PSC.EDU by www.ccl.net (8.6.9/930601.1506) id PAA10994; Tue, 10 Jan 1995 15:02:22 -0500 From: Date: Tue, 10 Jan 1995 15:02:40 -0500 (EST) To: chemistry@ccl.net Message-Id: <950110150240.20406087@B.PSC.EDU> Subject: NMR workshop offered by PSC STRUCTURE DETERMINATION USING NMR Pittsburgh Supercomputing Center June 25-28, 1995 Pittsburgh Supercomputing Center (PSC) is offering biomedical researchers a Structure Determination Using NMR Workshop. The objective is to introduce participants to the different techniques for the elucidation of solution structures of biological macromolecules from nuclear magnetic resonance data. The worskhop will consist of lectures and extensive hands-on sessions. The programs AMBER, Mardigras and MidasPlus will be discussed. Hands-on sessions will be emphasized. Participants will be able to work on the examples provided or on their own experimental data. No prior supercomputing experience is necessary. Workshop leaders are: Dr. David Case, The Scripps Research Institute; Dr. Thomas James, University of California, San Francisco; Dr. Julie Newdoll, Computer Graphis Laboratory, University of California, San Francisco; and Dr. Uli Schmitz, University of California, San Francisco. This workshop is funded by a grant from the Biomedical Research Technology Program, National Center for Research Resources, National Institutes of Health. Travel, meals and hotel accommodations for researchers affilated with U.S. academic institutions are supported by this grant. Enrollment is limited to 20. An application form is included. Deadline for applications is: April 28, 1995. * * * * * * * * * * PITTSBURGH SUPERCOMPUTING CENTER BIOMEDICAL INITIATIVE STRUCTURE DETERMINATION USING NMR June 25-28, 1995 APPLICATION Name:________________________________________________________________________ Affiliation:_________________________________________________________________ Address:_____________________________________________________________________ (Business) _____________________________________________________________________________ ____________________________________________________________________________ (Home) ____________________________________________________________________________ Telephone: ____________________ ______________________ (Business) (Home) *Social Security Number: _______-_____-_______ Citizenship: ____________ Electronic Mail Address:____________________________________________________ Status: ___Graduate ___Post-doctoral Fellow ___Faculty ___Other (specify) Please indicate specifically any special housing, transportation or dietary arrangements you will need: _______________________________________________ How did you learn about this workshop? _____________________________________ REQUIREMENTS: Applicants must submit a completed application form and a cover letter. The letter should describe, in one or two paragraphs, your current research and how participating in the workshop will enhance this research. Please include a brief statement describing your level of experience with computers. Faculty members, staff and post-docs should provide a curriculum vita. Graduate students must have a letter of recommendation from a faculty member. Please return all application materials by APRIL 28, 1995 to: Biomedical Workshop Applications Committee Pittsburgh Supercomputing Center 4400 Fifth Avenue, Suite 230C Pittsburgh, PA 15213 Direct inquiries to: Nancy Blankenstein, blankens@psc.edu or 412/268-4960. *Disclosure of Social Security Number is voluntary. PSC does not discriminate on the basis of race, color, religion, sex, age, creed, national or ethnic origin, or handicap. From srheller@probe.nalusda.gov Tue Jan 10 16:22:21 1995 Received: from cliff.nalusda.gov for srheller@probe.nalusda.gov by www.ccl.net (8.6.9/930601.1506) id OAA29193; Tue, 10 Jan 1995 14:53:46 -0500 Received: from probe.nalusda.gov by cliff.nalusda.gov (4.1/SMI-4.1) id AA01767; Tue, 10 Jan 95 14:56:14 EST Received: by probe.nalusda.gov (5.0/SMI-SVR4) id AA06044; Tue, 10 Jan 1995 14:46:52 +0500 Date: Tue, 10 Jan 1995 14:46:52 -0500 (EST) From: Steve Heller Subject: Software and Database for Review To: jcicshelp , chemistry@ccl.net, chminf-l@iubvm.ucs.indiana.edu, orgchem@extreme.chem.rpi.edu Message-Id: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII Content-Length: 4560 10 January, 1995 Subject: Computer Software for Review As the Software Review Editor for the ACS Journal of Chemical Information and Computer Science (JCICS) I often get software for review in the journal. I have 11 new software and database products. I am looking for people who are willing to review these software/databases products. In return for the review which is published in JCICS you get to keep the software or database. The review should be completed in 1-3 months. The length of the review is 4-10 double spaced typed pages. Sample reviews can be found in most of the recent issues of JCICS. Please try to give me some (short) reason to choose you over another person. DO NOT SAY YOU WILL REVIEW ANYTHING I HAVE AVAILABLE. Messages with such replies are trashed! I have tried this approach for about the past four years and it is working reasonably well. (REMINDER: For those who haven't finished your reviews of software sent months and months ago, this last sentence does not apply to you!) As a result, I am continuing this new method to find reviewers using this e- mail/user group system. I reserve the right to abandon this if it is a problem, or inappropriate. I will not notify people if I have found a reviewer. If you don't hear from me within a few days I have chosen someone else to review the particular package. As I get many, many, (too many) replies to this message, please do not respond after 12 January 1995 (Thursday), as I am sure the software will be gone by then. I can be reached on Internet (SRHELLER@ASRR.ARSUSDA.GOV or SRHELLER@PROBE.NALUSDA.GOV). PLEASE BE SURE TO INCLUDE AN STREET ADDRESS, PHONE, and FAX NUMBER!!! (I send the software by Federal Express.) Without this information I WILL NOT consider your request. Steve Heller The packages I now have are: 1. Derwent CD-ROM, Chemical Innovations Series: Food & Food Technology (January 1992 - June 1994). The CD-ROM comes from the Derwent World Patent Index (WPI) database. Requires a CD-ROM drive compatible with ISO9660 and an IBM compatible PC with Windows 3.1 or higher or DOS 3.0 or higher and 512Kb of available RAM. 2. Derwent CD-ROM, Chemical Innovations Series: Cosmetics (January 1992 - June 1994). The CD-ROM comes from the Derwent World Patent Index (WPI) database. Requires a CD-ROM drive compatible with ISO9660 and an IBM compatible PC with Windows 3.1 or higher or DOS 3.0 or higher and 512Kb of available RAM. 3. Derwent CD-ROM, Chemical Innovations Series: Household and General Cleaning (January 1992 - June 1994). The CD-ROM comes from the Derwent World Patent Index (WPI) database. Requires a CD-ROM drive compatible with ISO9660 and an IBM compatible PC with Windows 3.1 or higher or DOS 3.0 or higher and 512Kb of available RAM. 4.MLAB, DOS Version V from Civilized Software. MLAB is an advanced interactive system for mathematical and statistical modeling. It capabilities include curve-fitting, differential equations, statistics, and graphics. Requires DOS 3.x or higher, a 80486DX or high chip, a high density 3 1/2 high floppy drive, and 3 MB of hard disk space. 5. EndNote Plus2 for the Mac from Niles & Associates. Organizes your references and builds bibliographies in your word processor. Requires a Mac and System 6.02 or higher, a hard disk, and 750K of free memory. 6. EndLink for the Mac from Niles & Associates. Imports references downloaded from online services or CD-ROM's into EndNote Plus2. Requires a Mac and System 6.02 or higher, a hard disk, and 750K of free memory. 7. Gardners Electronic Handbook on CD-ROM for Windows from Ashgate Publishing. Requires an IBM PC or compatible with 2MB RAM, Windows 3.1 or higher or OS/2/2/1, a mouse, a CD-ROM drive. 8. Industrial Surfactants Electronic Handbook on CD-ROM for Windows from Ashgate Publishing. Requires an IBM PC or compatible with 2MB RAM, Windows 3.1 or higher or OS/2/2/1, a mouse, a CD- ROM drive. 9. Chemistry 4D-Draw , version 2.0 from ChemInnovation Software. This is the Mac version of the ChemNameStr program which converts names to structures. 10. ClogP, release 0.9.9b program for the Mac from BioByte. This is a program for calculating log P (octanol/water) partition coefficients. Requires a Mac with a 68020 or faster chip, and System 7, 1.9 Mb of hard disk , and 1Mb of memory. 11. British Pharmacopoeia (Veterinary), Version 1.0, on CD-ROM from UNIPUB. requires an IBM PC or compatible with a 80486 chip or higher and Windows 3.1 or higher. From CTARG@Levels.UniSA.Edu.Au Tue Jan 10 18:35:47 1995 Received: from Levels.UniSA.Edu.Au for CTARG@Levels.UniSA.Edu.Au by www.ccl.net (8.6.9/930601.1506) id RAA03092; Tue, 10 Jan 1995 17:50:51 -0500 From: Received: from Levels.UniSA.Edu.Au by Levels.UniSA.Edu.Au (PMDF V4.3-13 #6043) id <01HLPR7V01ZK90NQ2O@Levels.UniSA.Edu.Au>; Wed, 11 Jan 1995 09:20:07 +1030 Date: Wed, 11 Jan 1995 09:20:07 +1030 Subject: Example in Mopac 93.00 manual, pages 118 - 123 To: chemistry@ccl.net Message-id: <01HLPR7V275E90NQ2O@Levels.UniSA.Edu.Au> X-Envelope-to: chemistry@ccl.net X-VMS-To: IN%"chemistry@ccl.net" MIME-version: 1.0 Content-type: TEXT/PLAIN; CHARSET=US-ASCII Content-transfer-encoding: 7BIT Hi Netters, I have been using Mopac 93 for a while now and foolishly decided to work through the example given on pages 118 to 123 of the manual. I have a two rather simplistic but important questions: Is there any method of diagonalising the intial fock matrix (pg 121) by hand? and How is the density matrix calculated on page 122? I have spent the last two days studying various quantum mechnical texts but they include a lot of theory and very little numerical technique. Books on matrices contain huge amounts of theroms and proofs but are rather short on worked examples. Any help or pointers would be appreciated. Thanks Andy. From kevin@rose.chem.wesleyan.edu Tue Jan 10 18:45:54 1995 Received: from rose.chem.wesleyan.edu for kevin@rose.chem.wesleyan.edu by www.ccl.net (8.6.9/930601.1506) id SAA27132; Tue, 10 Jan 1995 18:22:58 -0500 Received: by rose.chem.wesleyan.edu (AIX 3.2/UCB 5.64/4.03) id AA14728; Tue, 10 Jan 1995 18:14:01 -0500 Date: Tue, 10 Jan 1995 18:14:01 -0500 Message-Id: <9501102314.AA14728@rose.chem.wesleyan.edu> From: kevin@rose.chem.wesleyan.edu (Kevin McConnell) To: srheller@probe.nalusda.gov Cc: chemed-l@uwf.cc.uwf.edu, chemistry@ccl.net, chminf-l@iubvm.ucs.indiana.edu, orgchem@extreme.chem.rpi.edu In-Reply-To: (message from Steve Heller on Tue, 10 Jan 1995 14:46:52 -0500 (EST)) Subject: Re: CCL:Software and Database for Review Steve, I would be very interested in trying out the new endnote and endlink programs. I think you might agree that the two need to evaluated together. Any way I am a fourth year graduate student at Wesleyan University working in the area of Molecular Biophysics with Dr.Dave Beveridge. I have been using endnote for the past four years now and I am extreemly familar with endnote and plug-in module for Word. I am currently working on sections of my thesis and will be importing references I have gotten from STN a Chem. Abst. data base so I would like to use both programs. Thank You for your time and attention Kevin McConnell Wesleyan University Department of MB&B Lawn Ave Middletown CT. 06459 phone (203) 685-2777 fax (203) 685-2211 5. EndNote Plus2 for the Mac from Niles & Associates. Organizes your references and builds bibliographies in your word processor. Requires a Mac and System 6.02 or higher, a hard disk, and 750K of free memory. 6. EndLink for the Mac from Niles & Associates. Imports references downloaded from online services or CD-ROM's into EndNote Plus2. Requires a Mac and System 6.02 or higher, a hard disk, and 750K of free memory. From mercie@mail.med.cornell.edu Tue Jan 10 18:54:53 1995 Received: from mail.med.cornell.edu for mercie@mail.med.cornell.edu by www.ccl.net (8.6.9/930601.1506) id RAA02151; Tue, 10 Jan 1995 17:50:17 -0500 Received: (from mercie@localhost) by mail.med.cornell.edu (8.6.9/ech1.75) id RAA06438; Tue, 10 Jan 1995 17:50:08 -0500 Date: Tue, 10 Jan 1995 17:50:06 -0500 (EST) From: Gustavo Mercier To: "Ellen R. Laird" cc: chemistry@ccl.net Subject: Re: CCL:Kd vs IC50 In-Reply-To: <9501101813.AA20852@nautilus.ariad.com> Message-ID: MIME-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII On Tue, 10 Jan 1995, Ellen R. Laird wrote: > ... < several lines cut-off > > > If this ratio equivalence has not been demonstrated (i.e., K_n have not > been measured in a comparable assay), is there a general relationship > that can be drawn between IC50 and Kd? A general relationship cannot be developed for drug - membrane receptor interactions. When assumptions are made about the nature of the drug (i.e. agonist, partial agonist, antagonist) and the properties of the receptor (i.e. type of transduction mechanism) you can develop a relationship between the IC50 and the Kd. See a reference below. Unfortunately, many times this requires more knowledge of the receptor system that actually be available. > > I have read a straightforward treatment of this *for enzymes* by Cheng > and Prusoff (Biochemical Pharmacology, 1973, 22, 3099 - thanks to Dr. > James Blake of Pfizer Central Research for supplying this reference); > according to their analysis, Kd for an inhibitor is equal to the IC50 > only when noncompetitive or uncompetitive kinetics apply. Noncompetitive or uncompetitive? I would have expected it from competitive kinetics, but I have not read their paper! > Unfortunately, I am dealing with binding to non-catalytic > protein domains; it is not clear to me how one could extend > the Cheng and Prusoff arguments to compounds that simply inhibit > receptor-ligand interactions. I would suggest that you read articles in pharmacodynamics. A book by T. Kenakin (I'll get back to you with the full reference) is very useful and has a good set of references. > > On a related issue - it is evident from the literature that the > majority of researchers in medicinal chemistry use a direct comparison > of IC50 values as sufficient for determining the relative efficacy > among a set of inhibitors; other than a desire to validate ddG > computed by via sophisticated simulations, do computational chemists > involved in pharmaceutical research even care to consider IC50 > data in terms of free energy relationships? > IC50 are used for convenience and basically necessity. In many instances medicinal chemists deal with membrane bound receptors coupled to a transducer system that complicates the kinetics of binding. Many times, the molecular nature of the membrane bound receptor is simply unknown. Are you dealing with the simple protein, or the protein coupled to its transducer, another protein. For example, in the case of membrane receptors coupled to the G-proteins, the Kd of the agonist is dependent on the presence of GTP because in the presence of the agonist the receptor binds the transducer which exists in two states, a GDP bound form and a GTP bound form, each with different Kd's. In the case of antagonists the binding of the receptor to the transducer protein does not occur and the kinetics are simpler. In this case the IC50 reflects the Kd. Finally, in pharmacology you must make the difference between a binding site interrogated using a binding experiment where IC50's are reported, and a dose -response curve that interrogates a receptor where EC50's are reported. A binding site is not necessarily a receptor and is necessary to show that a given binding experiment does interrogate a receptor defined on the basis of a dose - response curve. It is not enough to simply use the same pharmaceuticals in both experiments. The same complications that occur with associating IC50 to Kd's occur with associating EC50 to Kd's (may be worse due to issues of receptor reserve etc.) These complications have led pharmacologists to report EC50 and IC50 rather than Kd's. You may wonder why not define the kinetics through suitable kinetic experiments. Unfortunately, for membrane receptors kinetic experiments are difficult because the rate limiting step may be the diffusion of the drug into the membrane. If you are curious about this topic, I would suggest that you get in touch with Dr. Roman Osman (Mount Sinai School of Medicine, NY, NY. Dept. of Physiology and Biophysics and of Pharmacology). Several years ago, one of his students (Robert Cory) wrote a thesis on the kinetics of either an adrenergic or serotonergic receptor. They worked out the details necessary to show that the observations were not a reflection of the diffusion across membranes. In spite of these limitations, EC50's are many times taken as a reflection of Kd's by computational chemists. The assumption is that the rank order of the EC50's will reflect the rank order of the Kd's. Good Luck! G. A. Mercier, Jr. mercie@mail.med.cornell.edu From mercie@mail.med.cornell.edu Tue Jan 10 19:35:54 1995 Received: from mail.med.cornell.edu for mercie@mail.med.cornell.edu by www.ccl.net (8.6.9/930601.1506) id TAA21047; Tue, 10 Jan 1995 19:31:52 -0500 Received: (from mercie@localhost) by mail.med.cornell.edu (8.6.9/ech1.75) id TAA11116; Tue, 10 Jan 1995 19:31:50 -0500 Date: Tue, 10 Jan 1995 19:31:50 -0500 (EST) From: Gustavo Mercier To: "Ellen R. Laird" cc: chemistry@ccl.net Subject: Re: CCL:Kd vs IC50 follow up In-Reply-To: <9501101813.AA20852@nautilus.ariad.com> Message-ID: MIME-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII Hi! Here is the reference I promised with a few more added: 1)Pharmacologic Analysis of Drug - Receptor Interaction T. P. Kenakin Raven Press, New York 1987 This book is limited to the analysis of dose - response curves, but response is related occupation through the "stimulus function". It also includes some kinetics of dose -response curves and a chapter on the diffusion of drugs across membranes in a tissue preparation. 2)Protein Interactions G. Weber Chapman and Hall, New York 1992 A rather advanced treatment of protein - small ligand and protein - protein binding. Together with (1) you can appreciate the complexity of relating an IC50 or EC50 to a Kd value in the absence of information on the chemical nature of the receptor. Below are some papers relevant to the topic: An accurate method for determination of receptor - ligand and enzyme - inhibitor dissociation constants from displacement curves. A. Horowitz and A. Levitzki, Proc. Natl. Acad. Sci, USA v. 84, pp. 6654-6658 1987. This is a generalization of the binding equations by eliminating some of the usual assumptions about the concentrations of the ligand vs the concentration of the "receptor". Estimation of the Affinities of Allosteric Ligands Using Radioligand Binding and Pharmacological Null Methods. F. J. Ehlert, Molecular Pharmacology 33: 187-184, 1988. This paper addresses the extraction of affinity constants from dose - response curves in the case when a receptor exhibits allosteric binding. The hard thing is realizing that your receptor does exhibit allosteric binding when the ligand affecting the binding of the drug is a molecule available in the in vivo state. In this case, the method of tissue preparation would affect both the binding curves and the dose - response curve if the methods differ in their ability to retain the native molecule responsible for the allosteric binding. The Binding Capacity is a Probability Density Function. E. Di Cera and Z.-Q. Chen, Biophysical Journal. v. 65 pp. 164-170 (1993) A paper of more interest to computational chemist who attempt to relate binding data to thermodynamic (MC,MD,BD) simulations. By way of reference 2 above you could link this paper to reference 1, but this is only speculation on my part and I cannot give you the steps to do so! Any takers on this one! Good Luck! Gustavo A. Mercier, Jr. mercie@mail.med.cornell.edu