From san@mbu.iisc.ernet.in Fri Jan 20 02:38:25 1995 Received: from sangam.ncst.ernet.in for san@mbu.iisc.ernet.in by www.ccl.net (8.6.9/930601.1506) id CAA13516; Fri, 20 Jan 1995 02:03:42 -0500 From: Received: from iisc.ernet.in (iisc.iisc.ernet.in [144.16.64.3]) by sangam.ncst.ernet.in (8.6.8.1/8.6.6) with SMTP id MAA05178 for ; Fri, 20 Jan 1995 12:32:49 +0530 Received: from vigyan.UUCP by iisc.ernet.in (ERNET-IISc/SMI-4.1) id AA01536; Fri, 20 Jan 95 12:37:57+0530 Date: Fri, 20 Jan 95 12:37:57+0530 Message-Id: <9501200707.AA01536@iisc.ernet.in> Received: by vigyan.iisc.ernet.in (smail2.3) id AA25621; 20 Jan 95 12:33:04 EST (Fri) To: vigyan!chemistry@ccl.net Subject: coputational biophysics Hi! Last week i had asked a question about existence of separate network for data analysis of large biomolecules. Here is the summary of messages i recieved in response. If anybody wants to recieve the answers separately, please let me know at san@mbu.iisc.ernet.in sandeep kumar MBU, IISc. Bangalore INDIA. Hi Sandeep, There is a newsgroup of your interesting field. It is bionet.xtallography. And the mailing list PROTEIN-CRYSTALLOGRAPHY of bionet. May this will help you. Regards, Dawei ------------------------------------------------------------------- Dawei LIN Room 115, Building 27 Peking University Beijing 100871 Doctoral Candidate of P.R.China Chemistry Department ldw@pchindigo2.ipc.pku.edu.cn Dawei LIN (86)-1-2501490 tel Institute of Physical Chemistry (86)-1-2501725 fax Peking University Beijing 100871 P.R.China -------------------------------------------------------------------- Dear colleague, as I share with you the interest for a such possible list, I would appreciate if you could forward to me the answers you will get from the CCL about your question. Many thanks in advance. Maurizio Bronzetti --------------------------------------- Maurizio Bronzetti, Dr. Sr Scientist - Pharmaceutical Sector MDL Information Systems Inc. 14600 Catalina Street San Leandro, 94577 CA USA FAX: +1-510-483-4738 Tel: +1-510-8951313 ext. 1236 E-mail: mauriziob@mdli.com --------------------------------------- try xtal-log.bionet send a mail to biosci-server@net.bio.net and put in the body help end that will give you more information how to subscribe to xtal-log.bionet Godd luck, -- ================================================================== Dr. Nick Blom Tel : +1-514-3436111 ext 5352 Departement de Biochimie Fax : +1-514-3432210 Universite de Montreal Email: nick@bch.umontreal.ca C.P. 6128, Station Centre-Ville Montreal, PQ, H3C 3J7 Canada ================================================================== please let me know what you find out. thanks tom +------------------------------------------------- |doctoral candidate |Theoretical Biophysics bishop@ks.uiuc.edu |Beckman Institute Tel: (217)-244-1851 |University of Illinois fax: (217)-244-6078 |405 N Mathews, Urbana, IL61801 NeXTmail Ok | +-------------------------------------------------- On Sat, 14 Jan 1995 san@mbu.iisc.ernet.in wrote: > Hi! > can anybody tell me whether there exists a separate network for the > people who analyze the crystal or nmr structure data for large > biological macromolecules e.g. proteins, DNA etc. > please send your replies either to this > net or personally to me > san@mbu.iisc.ernet.in > > sandeep kumar x> MBU, IISc., Bangalore, >xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx Dear Dr. Kumar, could you please forward the listing for these networks when you compile them I am interested in the same subjects. thank you in advance. Tony Lackey - anlackey@blue.weeg.uiowa.edu Here are some addresses: * The PDB discussion list: pdb-l@pdb.pdb.bnl.gov. Send a message containing "help" to: listserv@pdb.pdb.bnl.gov * Usenet discussion groups: bionet.biology.computational, bionet.molec-model, bionet.molbio.proteins, bionet.structural-nmr, bionet.xtallography Good luck! -- | Ton Rullmann NMR Spectroscopy | | Bijvoet Center for Biomolecular Research | Tel. : int+31.30.533641 | | Utrecht University, Padualaan 8, | Fax : int+31.30.537623 | | 3584 CH Utrecht, The Netherlands | Email: rull@nmr.chem.ruu.nl | From JeanLuc.Verschelde@rug.ac.be Fri Jan 20 03:38:07 1995 Received: from mserv.rug.ac.be for JeanLuc.Verschelde@rug.ac.be by www.ccl.net (8.6.9/930601.1506) id DAA14135; Fri, 20 Jan 1995 03:14:47 -0500 Received: from allserv.rug.ac.be by mserv.rug.ac.be with SMTP id AA29237 (5.67b/IDA-1.5 for ); Fri, 20 Jan 1995 09:13:50 +0100 Received: by allserv.rug.ac.be (5.0/SMI-SVR4) id AA03200; Fri, 20 Jan 1995 09:14:15 +0100 Date: Fri, 20 Jan 1995 09:14:14 +0100 (MET) From: Jean-Luc Verschelde To: OHIO SUPER Subject: help e-mail Message-Id: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII Content-Length: 813 Hi all, Can someone help me to find the e-mail addresses of Gerald Bohm or Rainer Jaenicke. I tried but did not succeed. Thanks, Jean-Luc =================================================================================== Verschelde Jean-Luc University of Ghent Lab. for Mathematical Physics | Lab. for Biochemistry | Krijgslaan 286 S9 | K.L. Ledeganckstraat 35 9000 Ghent | 9000 Ghent Belgium. | Belgium. Tel.:09/264 47 94 Fax:09/264 49 89 Email:Jeanluc.Verschelde@rug.ac.be =================================================================================== From silver.ch.unito.it@ch.unito.it Fri Jan 20 04:38:06 1995 Received: from SILVER.CH.UNITO.IT for silver.ch.unito.it@ch.unito.it by www.ccl.net (8.6.9/930601.1506) id EAA14746; Fri, 20 Jan 1995 04:28:15 -0500 Message-Id: <199501200928.EAA14746@www.ccl.net> Received: from chpc02.ch.unito.it by SILVER.CH.UNITO.IT with SMTP; Fri, 20 Jan 1995 10:33:30 +0100 (WET) Date: Wed Jan 18 10:31:07 1995 From: silver.ch.unito.it@ccl.net To: chemistry@ccl.net Subject: Proton Affinities of simple molecules Mime-Version: 1.0 Content-Type: text/plain; charset=us-ascii X-Mailer: Cc: ugliengo@silver.ch.unito.it Dear Netters, does anybody know where I can find a good collection of Proton Affinities for some simple molecules, namely: HCCH, Me-CCH, Et-CCH, Me-CC-Me H2CCH2, Me-CCH2. Values can be both experimental and computed by good quality ab-initio methods. I will also appreciate to know any collection available via the net. Thanks in advance to all reading and answering this mail Best wishes Piero Ugliengo Dip. Chimica Inorganica Univ. Torino Via P. Giuria, 7 I-10125 Torino E-Mail: ugliengo@silver.ch.unito.it From ivarm@boc.ic.ee Fri Jan 20 05:38:08 1995 Received: from argus.chemnet.ee for ivarm@boc.ic.ee by www.ccl.net (8.6.9/930601.1506) id EAA14905; Fri, 20 Jan 1995 04:48:05 -0500 Received: from boc.ic.ee (boc.ic.ee [193.40.250.200]) by argus.chemnet.ee (8.6.9/8.6.9) with SMTP id LAA04623 for ; Fri, 20 Jan 1995 11:42:22 +0200 Received: from argus.chemnet.ee by boc.ic.ee id aa09732; Fri, 20 Jan 95 11:48:13 estonia From: "Ivar Martin" Date: Fri, 20 Jan 95 11:46:51 EST Message-Id: <1995.ivarm@boc.ic.ee_POPMail/PC_3.2.2> Reply-To: X-POPmail-Charset: English To: chemistry@ccl.net Subject: Molecular Dynamics for MOPAC Hi, 1) does anyone know how to run molecular dynamics with MOPAC 6.0 like one can run it in HyperChem (combining AM1, PM3 etc. with molecular dynamics simulation). 2) Is there a general concept how to find global energy minimum by molecular dynamics simulation. Overview references would be great. Thanks _______________________________ Ivar Martin, Department of Bioorganic Chemistry tel: +372 2 526510 Institute of Chemistry fax: +372 2 536371 Akadeemia tee 15 EE0026 e-mail: ivarm@boc.ic.ee Tallinn, ESTONIA From arthur@pchindigo2.IPC.PKU.EDU.CN Fri Jan 20 06:38:08 1995 Received: from pchindigo2.IPC.PKU.EDU.CN for arthur@pchindigo2.IPC.PKU.EDU.CN by www.ccl.net (8.6.9/930601.1506) id GAA15529; Fri, 20 Jan 1995 06:33:26 -0500 Received: by pchindigo2.IPC.PKU.EDU.CN (920330.SGI/911001.SGI) for chemistry@ccl.net id AA06919; Fri, 20 Jan 95 19:22:25 +0800 Date: Fri, 20 Jan 1995 19:22:25 +0800 (SST) From: Wan Arthur To: chemistry@ccl.net Subject: Summary of Info. on Cellular Automata Message-Id: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII Dear Netters, About a week ago, I put forward the question "Anyone interested in cellular automata?". Now I would like to offer the summary of the responses I have received. Forgive me for having not said "Thanks" respectively to each person who helped me. Here I show my real appreciation and thanks. The summary is by no means abundant. Maybe it serves right to prove that the applications of cellular automata to chemistry and biology is still in its infant. Let's develope it! Best Wishes. Arthur ----------------------------------------------------------------------------- From: DTCCM@jazz.ucc.uno.edu Arthur, A collection of papers entitled "Cellular Automata and Complexity" is available from Addison-Wesley (ISBN 0-201-62664-0) Tel. (USA) 617.944.9338 -Don Don Coupe University of New Orleans ----------------------------------------------------------------------------- From: rull@rhino.chem.ruu.nl (Ton Rullmann) A lot is going on in this field, although I am not sure how relevant most of this is to chemistry and biology in their current states. Some interesting Web-pages I found are: * http://www.seas.upenn.edu/~ale/cplxsys.html An Attempt To (Really) Tie Complex Systems Together * http://alife.santafe.edu/alife/software/ Artificial Life software * http://www.cs.cmu.edu:8001/afs/cs.cmu.edu/project/ai-repository/ai/html/air.html CMU Artificial Intelligence Repository * http://lenti.med.umn.edu/~mwd/md_hotlist.html A personal hotlist with many refs. And of course there are various Usenet discussion groups, such as comp.ai.alife, comp.ai.genetic, comp.ai.neural-nets, comp.theory.cell-automata. -------------------------------------------------------------------------------- From: Frank Herrmann Dear Mr.Wang, a few minutes ago I was pointed to a world wide web page (xmosaic): http://www.santafe.edu/projects/evca its not exactly what you are looking for but maybe its related ... ------------------------------------------------------------------------------ From: DTCCM@jazz.ucc.uno.edu Dear Mr. Wang, I, too, am interested in Cellular Automata and its application to chemistry. There is a collection of papers by Steven Wolfram. I will forward the name of the publisher and ISBN number later. Also try "FTP.ALIFE.SANTAFE.EDU" -Don Coupe University of New Orleans email = "dtccm@uno.edu" ------------------------------------------------------------------------------ From ellen@nautilus.ariad.com Fri Jan 20 08:39:29 1995 Received: from ariad.com for ellen@nautilus.ariad.com by www.ccl.net (8.6.9/930601.1506) id IAA16627; Fri, 20 Jan 1995 08:07:32 -0500 Received: from nautilus.ariad.com by ariad.com (4.1/4.1-NEARnet) id AA09690; Fri, 20 Jan 95 08:08:38 EST Received: by nautilus.ariad.com (931110.SGI/930416.SGI) for @ariad.ariad.com:chemistry@ccl.net id AA14927; Fri, 20 Jan 95 08:08:24 -0500 From: ellen@nautilus.ariad.com (Ellen R. Laird) Message-Id: <9501201308.AA14927@nautilus.ariad.com> Subject: IC50 vs. Ki summary To: chemistry@ccl.net Date: Fri, 20 Jan 95 8:08:24 EST Reply-To: Organization: ARIAD Pharmaceuticals, Inc. X-Mailer: ELM [version 2.3 PL11] Greetings: Recently I posted a query regarding comparisons between IC50 and Ki data for receptor/ligand binding. The original post and a summary of responses follows. Many thanks to the respondents for several in-depth replies. And now for related survey: is there a consensus in the drug discovery community as to what constitutes an acceptable degree of variance in data for binding assays (i.e., "simple" ligand::protein binding experiments, not cell- or tissue- based). I am especially interested in the experiences of others in the pharmaceutical industry who are trying to establish SAR. Thanks in advance, and I'll post a summary. - Ellen ------------------------------------------------------------------------------- ~~~~~~ ~~~~~~~~ Ellen R. Laird ~~~~~~~~~~ ellen@ariad.com ~~~~~~~~~~ ~~~~~~~~ ~~~~~~ARIAD Pharmaceuticals, Inc. 26 Landsdowne St. Cambridge MA 02139 (617) 494-0400, ext 234 fax: 494-8144 ------------------------------------------------------------------------------- ============== Original Post: ============== 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? Thanks in advance; I'll post a summary of responses. - Ellen ========== RESPONSES: ========== ------------ From MARTIN%cmda@randb.abbott.com Tue Jan 10 15:32:01 1995 You might find some help in Terrence Kenakin "Pharmacologic Analysis of Drug-Receptor Interaction". Raven, New York, 1987. The whole book is devoted to dose-response curves and their analysis & interpretation. I would guess that if you have not only the IC50, but also the individual data points, you might be able to do something with the information. It certainly is better to vary both the compound of interest and the competing ligand & calculate a Kd that way. However, many folks calculate a Kd assuming/but not telling us explicitly/ competitive behavior. My philosophy as a modeler/QSAR practictioner is to use whatever data is being used to make decisions in a project as to whether to carry a compound further or drop it. If it is good enough for such important things, then it is good enough for our crude models. However, how closely a model should agree with an observation will be determined by how closely the experiment measures what the model purports to calculate. Sometimes, however, the biologist can easily supply data that corresponds to our model and is only to happy that someone wants to see it. So, you must understand the details and limitations of the biological measurements, and then use what you can get. Yvonne Martin Abbott Laboratories ------------- From murphy@cns.NYU.EDU Tue Jan 10 17:27:55 1995 Dear Dr. Laird: I am replying to your post today discussing several matters related to the question of equivalence of IC50 values and Ki values. I am a chemist who has worked in matters related to pharmacology for some time, and the following points might be useful to consider: In general your reservations about the Cheng-Prusoff treatment are correct. However, consider that the determination of an IC50 value involves (generally) the incubation of a radioligand with a receptor preparation of some sort. The binding isotherm must thus be saturable and the binding must in principle be to a single site. These are the basic assumptions of the Scatchard isotherm which are de facto the assumptions involved in determining an IC50. Rather more correctly, one could state that while one could certainly measure an IC50 value if the assumptions of the Scatchard isotherm were violated it would not be valid to compare relative avlues of IC50 the way people normally do. Thus, the point which I am trying to make here is that the whole idea of attempting to equate IC50 values to a delta,delta G is fine in a system where the assumptions of equilibrium binding are not violated, that is: 1. All the sites are identical and have identical affinity 2. All of the sites do not interact with one another as a function of fractional occupancy (e.g., no allosteric interaction). But in ANY other situation, the comparison isn't correct. How incorrect is a good question which has not been frequently addressed. In fact, if you read Scatchard's old papers he was mostly interested in binding of charged ions to serum albumin, in which allosteric interaction wasn't the problem but simple charge interaction was. I would refer you to C. Tanford's old Biophysical Chemistry text for the derivation of these equations. Tanford discusses some quite elegant extensions of free energy calculations for binding situations in which multiple ions can bind and interact on a protein surface using analytical (before computers!!!) solutions of the Poisson-Boltzmann equation. Thus, the bottom line would seem to me to be that if you can describe a model for the interaction of you multiple binding sites, even if it is a very simplistic one, then you can readily fit bidning and competetion data to it. Of course, if you have no idea what the interaction is, you could still probably model it by fitting to a sum of multiple Kis. The problem that you will immediately face is that the quality of the binding data will not allow you to distinguish between multiple models. Ultimately, this is the problem that we faced in our systems; that binding data generally just are not of a quality to enable more that the usual semi-quantitative comparisons. Even running fifty-point displacements (and we sometimes do!!) barely will give you the precision you need to distinguish models. Thus my advice would be to measure IC50 values, convert them to Ki values, and not worry too much about it provided that you are well aware of the assumptions involved. Perhaps if you really have a cloned, purified receptor and can do microcalorimetry on it then you can get reliable themrmodynamic data on it. Other references; Molinoff and cowhokers wrote a couple of papers about ten (12?) years ago in which they calculated thermodynamic data from binding data for a series of drugs which bound the the beta-adrenoceptor (I think beta-1). If you're interested I can find the ref. in my files or someplace here. As far as I know, this is the only decent attempt to do this for a real receptor. He made some interesting conclusions which were a little simplistic but thought- provoking about " entropic" versus "enthalpic" contributions. We are extremely interested in general in the questions that you raise and would welcome more discussion of them amongst pharmacologists. best regards Randy murphy ******************************************************************************** Randall B. Murphy, Ph.D. Murphy@cns.nyu.edu or Murphy@acfcluster.nyu.edu Associate Professor of Chemistry and Neural Sciences New York University, Washington Square, New York, NY 10003 USA Tel. 914-591-7573; 212-998-8433; FAX 212-260-7905 ******************************************************************************** -------------- From mercie@mail.med.cornell.edu Tue Jan 10 17:51:37 1995 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 IJZERMAN@rulgca.LeidenUniv.nl Wed Jan 11 03:20:02 1995 Dear Ellen: According to Cheng and Prusoff IC50 values can be converted to Ki values also under 'competitive' conditions. They say Ki = IC50/(1 + [L]/Kd) L stands for the concentration of the marker in your assay (usually a radio- ligand), and Kd for its (the radioligand's) affinity towards the protein (often a receptor). Beware that Ki relates to the affinity of the 'cold' (i.e. non-radiolabelled) ligand, and Kd to the affinity of the marker. Now to your question: the comparison of two IC50 values. >From the above it is evident that if the experimental conditions are the same (i.e. same radioligand concentration, same receptor preparation, etc) IC50 values are directly comparable to Ki values. You should check with the pharmacologists/biochemists whether this is indeed the case. I give you one reference of our research group that uses Ki and IC50 values in modeling studies, in which we deal with free energies, etc.: Van der Wenden et al, Eur J Pharmacol - Mol Pharm Sect 206 (1991) 315 - 323. Hope this helps, Ad IJzerman Leiden/Amsterdam center for drug research PO Box 9502 2300RA Leiden The Netherlands ijzerman@rulgca.LeidenUniv.nl ----------- From: Gustavo Mercier 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 ----------------- From IJZERMAN@rulgca.LeidenUniv.nl Wed Jan 11 03:20:02 1995 Dear Ellen: According to Cheng and Prusoff IC50 values can be converted to Ki values also under 'competitive' conditions. They say Ki = IC50/(1 + [L]/Kd) L stands for the concentration of the marker in your assay (usually a radio- ligand), and Kd for its (the radioligand's) affinity towards the protein (often a receptor). Beware that Ki relates to the affinity of the 'cold' (i.e. non-radiolabelled) ligand, and Kd to the affinity of the marker. Now to your question: the comparison of two IC50 values. >From the above it is evident that if the experimental conditions are the same (i.e. same radioligand concentration, same receptor preparation, etc) IC50 values are directly comparable to Ki values. You should check with the pharmacologists/biochemists whether this is indeed the case. I give you one reference of our research group that uses Ki and IC50 values in modeling studies, in which we deal with free energies, etc.: Van der Wenden et al, Eur J Pharmacol - Mol Pharm Sect 206 (1991) 315 - 323. Hope this helps, Ad IJzerman Leiden/Amsterdam center for drug research PO Box 9502 2300RA Leiden The Netherlands ijzerman@rulgca.LeidenUniv.nl -------- From pazhanisamy@macnet.vpharm.com Thu Jan 12 10:51:45 1995 I saw your note asking for clarification and use of IC50 values. For classical inhibitors exhibiting simple Michelis - Menton kinetics, the IC50 values are always proportional to Ki (or Kd) values and the proportionality constant is dependent on the concentration of the substrate ( or ligand) used in the experiment. Here are the exact relationships between IC50 and the Ki values for the standard mechanisms one encounters: competitive binding: IC50 = Ki*(1+S/Km) Non-competitive binding: IC50 = Ki Un-competitive binding: IC50 = Ki*(1+Km/S) For ligand binding studies replace S and Km with L and Kd, respectively. Therefore, the ratio of IC50 values should be exactly same as the ratio of the corresponding Ki ( or Kd) values provided the IC50 values were obtained under identical conditions. So, it is perfectly alright to deduce the free-energy differences between two compounds from their IC50 values. Hope, this is of some help.If you have any further questions please feel free to write to me or contact me at 499-2457. -Sam. --------- From: "Pazhanisamy" Hi Ellen, I sent you a message on this topic before. I hope you received it. I just want to qualify my statement as follws: "It is coreect to use the IC50 ratios in place of the Ki ratios provided both compounds observe the same simple Michelis-Menton kinetics." I am curious to know if you received any other responses. Thanks. My Email address is pazhanisamy@vpharm.com. -Sam. ---------- From S.MACFARLANE@elsevier.nl Fri Jan 20 12:38:15 1995 Received: from relay.surfnet.nl for S.MACFARLANE@elsevier.nl by www.ccl.net (8.6.9/930601.1506) id MAA20711; Fri, 20 Jan 1995 12:00:59 -0500 From: X400-Received: by /PRMD=surf/ADMD=400net/C=nl/; Relayed; Fri, 20 Jan 1995 17:58:26 +0100 X400-Received: by mta relay.surfnet.nl in /PRMD=surf/ADMD=400net/C=nl/; Relayed; Fri, 20 Jan 1995 17:58:26 +0100 X400-Received: by /PRMD=SURF/ADMD=400NET/C=NL/; converted (ia5-text); Relayed; Fri, 20 Jan 1995 15:52:33 +0100 Date: Fri, 20 Jan 1995 15:52:33 +0100 X400-Originator: S.MACFARLANE@elsevier.nl X400-Recipients: non-disclosure:; X400-MTS-Identifier: [/PRMD=SURF/ADMD=400NET/C=NL/;G00002E5820JAN199517502185] X400-Content-Type: P2-1984 (2) Content-Identifier: Elsevier's Elect Alternate-Recipient: Allowed Message-ID: To: chemistry@ccl.net Subject: Elsevier's Electronic Catalogue Looking for information? Now at your fingertips, an Internet Catalogue from the world's largest supplier of scientific and technical information. The complete Elsevier Science Catalogue is now available by Gopher and on World Wide Web Servers to any individual who has access to the internet. Not only does this feature all journals, books, major reference works, and newsletters, but it also allows you to access information about any of the electronic and CD-ROM products now published by Elsevier Science. Features Include: --> alerting facility for new and forthcoming publications --> monthly update --> product newsflashes --> electronic, CD-ROM products --> Elsevier Science's complete journal list (over 1100 titles) --> Elsevier Science's complete book list (over 5600 titles) --> subject classifications --> free text search facilities --> hypertext features --> ordering facilities --> download facilities for demos How to Access the Elsevier Science Servers: --> Gopher to: gopher.elsevier.nl --> WWW: http://www.elsevier.nl For chemistry-related inquiries please contact e.wezenbeek@elsevier.nl From elcana@iqm.unicamp.br Fri Jan 20 14:38:15 1995 Received: from clio.iqm.unicamp.br for elcana@iqm.unicamp.br by www.ccl.net (8.6.9/930601.1506) id OAA22852; Fri, 20 Jan 1995 14:17:01 -0500 Received: (elcana@localhost) by clio.iqm.unicamp.br (8.6.7/8.3) id RAA04032; Fri, 20 Jan 1995 17:16:50 -0300 From: Anselmo Elcana de Oliveira Message-Id: <199501202016.RAA04032@clio.iqm.unicamp.br> Subject: e-mail addresses To: CHEMISTRY@ccl.net Date: Fri, 20 Jan 1995 17:16:49 -0300 (GMT-0300) X-Mailer: ELM [version 2.4 PL23] Content-Type: text Content-Length: 341 Hi, Can someone help me to find the e-mail addresses of Anthony K. Rappe' (Colorado State University) and William A. Goddard III (California Institute of Technology). Please send it to me, not to the list. Thanks, Elcana elcana@iqm.unicamp.br Instituto de Quimica Universidade Estadual de Campinas - SP/Brazil From BILLINGS@UConnVM.UConn.Edu Fri Jan 20 15:38:15 1995 Received: from phem3 for BILLINGS@UConnVM.UConn.Edu by www.ccl.net (8.6.9/930601.1506) id PAA23906; Fri, 20 Jan 1995 15:04:19 -0500 Received: from UCONNVM.UCONN.EDU (MAILER@UCONNVM) by phem3.acs.ohio-state.edu (PMDF V4.2-13 #5888) id <01HM2NV1OQM88Y6IE5@phem3.acs.ohio-state.edu>; Fri, 20 Jan 1995 15:04:13 EDT Received: from UConnVM.UConn.Edu (BILLINGS) by UCONNVM.UCONN.EDU (Mailer R2.08 R208004) with BSMTP id 4153; Fri, 20 Jan 95 14:19:14 EST Date: Fri, 20 Jan 1995 14:18:40 -0500 (EST) From: Eric Billings Subject: Modeling counter-ions To: chemistry@ccl.net Message-id: <950120.141913.EST.BILLINGS@UConnVM.UConn.Edu> Content-transfer-encoding: 7BIT Hello netters ! When performing molecular modeling studies, the presence of counter-ions has a significant effect on both the dynamic trajectory and the energy of a single conformation. Adding counter-ions requires deciding on the number and location of the counter-ions. Do you have any references which would shed some light on the following questions: Have there been any recent studies of counter-ion placement in solution ? Is it possible to determine the number and location of representative counter-ions given a crystal structure which would incorporate the electrostatics of the enzyme ? I'll be happy to include references received with my own and post the results if there is sufficient interest. Thanks, Eric Billings Biophysics Graduate Student University of Connecticut billings@uconnvm.uconn.edu From randerso@ozarks.sgcl.lib.mo.us Fri Jan 20 16:38:22 1995 Received: from ozarks.sgcl.lib.mo.us for randerso@ozarks.sgcl.lib.mo.us by www.ccl.net (8.6.9/930601.1506) id QAA25185; Fri, 20 Jan 1995 16:23:38 -0500 Received: by ozarks.sgcl.lib.mo.us (4.1/SMI-4.1) id AA20807; Fri, 20 Jan 95 15:23:15 CST Date: Fri, 20 Jan 1995 15:23:14 -0600 (CST) From: "Robert E. Anderson" Sender: "Robert E. Anderson" Reply-To: "Robert E. Anderson" Subject: Novice To: chemistry@ccl.net Message-Id: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; CHARSET=US-ASCII Hi netters, I have been listening in on this mailing list for a few weeks now and have one minor request. Can someone recomend a message board for someone like me who is just starting into the chemistry field? I would appreciate any response either to myself or to the board. Any messages will be summerized and sent to CCL for other onlookers like myself. Thanks in advance, Rob Rob Anderson From jkl@ccl.net Fri Jan 20 16:44:58 1995 Received: for jkl@ccl.net by www.ccl.net (8.6.9/930601.1506) id PAA24715; Fri, 20 Jan 1995 15:50:14 -0500 Date: Fri, 20 Jan 1995 15:50:14 -0500 From: Jan Labanowski Message-Id: <199501202050.PAA24715@www.ccl.net> To: chemistry@ccl.net Subject: The Big Brother Coordinator is watching you Cc: jkl@ccl.net Dear Netters, This is just a reminder that the CCL list has rules. The rules are in the help file which is available by sending a message HELP CHEMISTRY to MAILSERV@ccl.net You can also get to it via WWW: http://www.ccl.net/chemistry.html through gopher (www.ccl.net port 73) and anon.ftp on www.ccl.net in /pub/chemistry/instructions/help And if somebody breaks the rules, I have to censor his/her messages. I do it by placing his/her address in a "reject" file. There are already 50 addresses in this file. If you happen to be the "chosen one", your message will have to wait for me to review it. And since I am busy, it can take some time. So please watch yourself, since I am watching you. If you think that I enjoy it, you are wrong. I hate it... It takes my time... Jan jkl@ccl.net -- Dr. Jan K. Labanowski, Senior Research/Supercomputer Scientist/Specialist, etc. Ohio Supercomputer Center, 1224 Kinnear Rd, Columbus, OH 43212-1163 ph:(614)-292-9279, FAX:(614)-292-7168, E-mail: jkl@ccl.net JKL@OHSTPY.BITNET From nmdl@rlmtc.DNET.hcc.com Fri Jan 20 17:38:18 1995 Received: from gatekeeper.hcc.com for nmdl@rlmtc.DNET.hcc.com by www.ccl.net (8.6.9/930601.1506) id QAA25509; Fri, 20 Jan 1995 16:47:28 -0500 From: Received: by gatekeeper.hcc.com (5.65/jj-092193); id AA03661; Fri, 20 Jan 95 16:47:25 -0500 Received: by mailgate.bridgewater.ne.hcc.com (5.65/ejc-092393< Who Loves Class M Planets>); id AA06622; Fri, 20 Jan 1995 16:43:36 -0500 Date: Fri, 20 Jan 1995 16:43:29 -0500 Message-Id: <9501202143.AA06622@mailgate.bridgewater.ne.hcc.com> To: "chemistry@ccl.net"@INET.DNET.hcc.com Subject: excited states Greetings, I am interested in computing the dipole moments of the first five excited states of a molecule. I have MOPAC and DMOL available. I would appreciate your suggestions as to the best way to proceed. Please be as detailed as you like, and include specific keywords or parametger settings that you have tried and has been sucessful. All the best, Sol Jacobson