From Jeffrey.Gosper@brunel.ac.uk Fri Dec 17 06:56:50 1993 Received: from sirius.brunel.ac.uk for Jeffrey.Gosper@brunel.ac.uk by www.ccl.net (8.6.4/930601.1506) id GAA22942; Fri, 17 Dec 1993 06:50:26 -0500 Received: from molnir.brunel.ac.uk by sirius.brunel.ac.uk with SMTP (PP) id <17493-0@sirius.brunel.ac.uk>; Fri, 17 Dec 1993 11:50:06 +0000 From: Jeffrey J Gosper Message-Id: <20776.9312171149@molnir.brunel.ac.uk> Subject: De Novo generation of lead compounds To: chemistry@ccl.net Date: Fri, 17 Dec 1993 11:49:55 +0000 (GMT) X-Mailer: ELM [version 2.4 PL21] Mime-Version: 1.0 Content-Type: text/plain; charset=US-ASCII Content-Transfer-Encoding: 7bit Content-Length: 613 Dear netters, I was discussing the role of computational chemistry/molecular modelling with the Director of Drug Discover with a small company yesterday and he was saying that he did not know of any drugs that have reached the market or clinical trials that were design De Novo from the tertiary structure of a receptor. Could those that know of such examples, or even where lead compounds have been developed by the same process, please notify me. If there are a reasonable number of examples I will summaries these on the net. Thanks Jeff Gosper Chemistry Dept. Brunel University From W695@emducm11.sim.ucm.es Fri Dec 17 07:56:51 1993 Received: from EMDUCM11.SIM.UCM.ES for W695@emducm11.sim.ucm.es by www.ccl.net (8.6.4/930601.1506) id HAA23291; Fri, 17 Dec 1993 07:55:49 -0500 Received: from EMDUCM11.SIM.UCM.ES by EMDUCM11.SIM.UCM.ES (IBM VM SMTP R1.2.2MX) with BSMTP id 2098; Fri, 17 Dec 93 13:53:27 GMT Received: from emducm11.sim.ucm.es (W695) by EMDUCM11.SIM.UCM.ES (Mailer R2.08 R208004) with BSMTP id 2097; Fri, 17 Dec 93 13:53:25 GMT Date: Fri, 17 Dec 93 13:47:23 GMT From: Mauricio Organization: Universidad Complutense de Madrid Subject: subscriber To: coordinator Message-Id: <931217.134723.GMT.W695@emducm11.sim.ucm.es> Madrid December 17th 1993 I would like to be included in your Computational Chemistry mailing list. Thanks. Mauricio Alcolea W695&EMDUCM11 From CHEM8@vax.york.ac.uk Fri Dec 17 08:56:51 1993 Received: from leeman.york.ac.uk for CHEM8@vax.york.ac.uk by www.ccl.net (8.6.4/930601.1506) id IAA23517; Fri, 17 Dec 1993 08:27:29 -0500 Via: uk.ac.york.vax; Fri, 17 Dec 1993 13:26:19 +0000 Date: Fri, 17 Dec 93 13:27 GMT From: "John Waite, Tel 1-7238958, N.H.R.F., Vas. Konstantinou 48, Athens 116-35" To: CHEMISTRY Subject: Nickel Diazalene, Structure and Calculations? Message-ID: <"leeman.yor.536:17.11.93.13.26.21"@york.ac.uk> Dear Netters, Does anyone know of references for the structure, bond lengths and angles of Nickel Diazalene, shown below? Also of calculations on the same system? H2 H2 R N N R R=H preferably \ / \ / \ / M=Ni || M || / \ / \ / \ R N N R H2 H2 Similarly for: H H2 R N N R R=H preferably \ / \ / \ / M=Ni || M || / \ / \ / \ R N N R H2 H or H2 H R N N R R=H preferably \ / \ / \\ / M=Ni || M | / \ / \ // \ R N N R H2 H and with four NH groups. Dr. John Waite, National Hellenic Research Foundation, Vas. Konstantinou 48, Athens GR116-35 GREECE E-mail: CHEM8@VAX.YORK.AC.UK From burkhart@goodyear.com Fri Dec 17 14:56:55 1993 Received: from goodyear.com for burkhart@goodyear.com by www.ccl.net (8.6.4/930601.1506) id OAA27438; Fri, 17 Dec 1993 14:46:53 -0500 Received: from rdsrv2 (rdsrv2.goodyear.com) by goodyear.com (4.1/SMI-4.1) id AA13807; Fri, 17 Dec 93 14:46:58 EST Received: from rds325 by rdsrv2 (4.1/SMI-4.1) id AA05001; Fri, 17 Dec 93 14:46:51 EST Received: by rds325 (920330.SGI/920502.SGI.AUTO) for chemistry@ccl.net id AA01938; Fri, 17 Dec 93 14:46:22 -0500 Date: Fri, 17 Dec 93 14:46:22 -0500 From: burkhart@goodyear.com (Craig W. Burkhart) Message-Id: <9312171946.AA01938@rds325> To: chemistry@ccl.net Subject: Anomalous PM3 Hydrogen Interactions Dear netters, We have a query regarding anomalously stable close contacts between nonbonded hydrogen pairs when using PM3. We would be interested in any comments regarding a problem we have encountered when using the semi-empirical method PM3. The simplest example of this problem is the formation of a "stable" "dimer" of methane. The geometry minimizes to a straight line between C-H ... H-C bonds in the dimer. This dimer possesses an apparent stabilization energy of about 2kcal/mole, with an H ... H separation distance of 1.7 Angstroms. We are concerned, as this effect is showing up in a host of crowded molecules--for example, t-butyl cyclohexane, or even in all-gauche conformation of n-pentane! We are not aware of any published discussion of this problem, but it is leading to what may appear to be erroneous geometries and heats of formation in many cases. Is this problem an inherent weakness of PM3? Are there satisfactory workarounds? Any references to discussions of this problem? Thanks in advance. Send all responses to cburkhart@goodyear.com, and we will summarize for the net... Sincerely, Eilert Ofstead and Craig Burkhart Goodyear Research -------------------------------------------------------------------------- Craig W. Burkhart, Ph.D. Senior Research Chemist E-mail: cburkhart@goodyear.com The Goodyear Tire & Rubber Co. Fone: 216.796.3163 Research Center Fax: 216.796.3304 142 Goodyear Boulevard Akron, OH 44305 -------------------------------------------------------------------------- For a successful technology, reality must take precedence over public relations, for Nature cannot be fooled - Feynman -------------------------------------------------------------------------- From rec@ncifcrf.gov Fri Dec 17 15:56:56 1993 Received: from fcs280s.ncifcrf.gov for rec@ncifcrf.gov by www.ccl.net (8.6.4/930601.1506) id PAA27964; Fri, 17 Dec 1993 15:26:08 -0500 From: Received: from fcindy5.ncifcrf.gov by fcs280s.ncifcrf.gov (4.1/NCIFCRF-3.0/AWF-2.0) id AA12612; Fri, 17 Dec 93 15:18:11 EST Received: by fcindy5.ncifcrf.gov (920330.SGI/911001.SGI) for @fcs280s.NCIFCRF.GOV:CHEMISTRY@ccl.net id AA19219; Fri, 17 Dec 93 15:25:58 -0500 Date: Fri, 17 Dec 93 15:25:58 -0500 Message-Id: <9312172025.AA19219@fcindy5.ncifcrf.gov> To: CHEMISTRY@ccl.net Subject: F77 Reply-To: cachau@ncifcrf.gov For those of you interested in the F77-GNU, you can request information by: finger -l fortran@gate.gnu.ai.mit.edu Good Luck R.E.Cachau _____________________________________________________________________________ Raul E. Cachau, National Cancer Institute Frederick Cancer Research and Development Center, PRI/DynCorp Structural Biochemistry Program and Frederick Biomedical Supercomputer Center Building 322, Room 19, P.O.Box B, Frederick, MD 21702-1201, USA Phone: +1-(301)-846-6062; Fax: +1-(301)-846-6066; e-Mail: cachau@ncifcrf.gov _____________________________________________________________________________ From hogue@canada.den.mmc.com Fri Dec 17 17:56:57 1993 Received: from canada.den.mmc.com for hogue@canada.den.mmc.com by www.ccl.net (8.6.4/930601.1506) id RAA29398; Fri, 17 Dec 1993 17:10:42 -0500 Received: by canada.den.mmc.com (4.1/1.34.a) id AA00848; Fri, 17 Dec 93 15:10:09 MST Date: Fri, 17 Dec 93 15:10:09 MST From: hogue@canada.den.mmc.com (Pat Hogue 1-2183) Message-Id: <9312172210.AA00848@canada.den.mmc.com> To: chemistry@ccl.net Subject: Program to predict XPS spectra Does anyone know if there is a program that predicts XPS spectral features? Valence level fluoroethers in particular? From AHOLDER@VAX1.UMKC.EDU Fri Dec 17 18:56:58 1993 Received: from VAX1.UMKC.EDU for AHOLDER@VAX1.UMKC.EDU by www.ccl.net (8.6.4/930601.1506) id SAA29863; Fri, 17 Dec 1993 18:03:18 -0500 Received: from VAX1.UMKC.EDU by VAX1.UMKC.EDU (PMDF V4.2-11 #4431) id <01H6LCMGUTTY9JIH45@VAX1.UMKC.EDU>; Fri, 17 Dec 1993 17:03:10 CST Date: Fri, 17 Dec 1993 17:03:10 -0600 (CST) From: Andy Holder Subject: De Novo Drug design To: CHEMISTRY@ccl.net Message-id: <01H6LCMGUTU09JIH45@VAX1.UMKC.EDU> X-VMS-To: IN%"CHEMISTRY@ccl.net" MIME-version: 1.0 Content-transfer-encoding: 7BIT Hi Netters! I read with interest an earlier question requesting info about some drugthat was designed from computational modelling. About two years ago, I asked for "semiempirical success" stories on thsi net and got a rather low response. Given my interest on a variety of fronts, I have been thinking about this for sometime. Please excuse the soapbox, but I would like to share some of my thoughts and those of others I have collected over the past few years on this issue: Drug companies and other chemical manufacturers are not going to tell you about this even if they have an example. This type of stuff is usually proprietary. Is this really the correct question to ask about computational chemistry (CC from here on)? What is it that we expect CC to accomplish for us? Is it going to replace experimental investigations? I look at CC in a company's product discovery cycle as a contributor to the process, not an end in itself. CC will NOT replace experimental information or procedures. We should not tell management (whether scientific or "lay") that it will. We should not try to sell it on this basis. The CC out there now is based on a set of models that are imperfect. These imperfections are present from molecular mechanics through semiempirical to ab initio methods. I admit they are getting better and more reliable (I work quite hard along these lines myself in the area of semiempirical methods) but they will never replace direct observations. How then should CC be viewed? I think an excellent analogy is the way we think about the analytical chemistry (AC) division of any large res- earch operation. AC supports efforts in all phases of the research process. However, the mass spec guy is never asked "What specific drug product is that there $500,000 GC/MS dohicky responsible for?" Everyone recognizes that the mass spec is part of the effort, and things would be crippled without it. This is how CC should be integrated into the research/discovery process. There are several models on how to include CC in a company's effort. In one, the CC guys are a consulting group that works with people that bring them specific problems. In another, each effort has one or more CC guys IN the group. Both are valid and both seem to be producing results. CC is good are predicting trends and in focusing experimental investigations, which are fairly expensive these days. CC should be part of every research problem in a modern setting. PART, I said, not WHOLE. Alot of the recent "backlash" against CC is due to overselling. If we CC folk expect to survive, we don't need to oversell the results that we can provide, but honestly point out what CC should be doing. To finish, I'll tell a little story. When I was interviewing for a job on leaving the Dewar group about 6 years ago, I visited the research labs of a large midwestern polymer manufacturer. I was shown a lab with 4 PhD polymer chemists in it. Each was required to make 1 new polymer blend per week. These blends then went to physical testing for evaluation as new products. The company expected to get one new CANDIDATE for a new product each year out of that lab. Seems a bit cost prohibitive doesn't it? They asked me how CC could help them. Back then, the answer was much less positive than it is now, but even then, CC could have helped them focus their efforts more directly and greatly enhanced the "hit rate." IMHO, that's what we do best. Hope this wasn't too preachy..... Andy Holder ps I welcome comments from others, especially our industrial brethren. =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-= DR. ANDREW HOLDER Assistant Professor of Computational/Organic Chemistry Department of Chemistry || BITNET Addr: AHOLDER@UMKCVAX1 University of Missouri - Kansas City || Internet Addr: aholder@vax1.umkc.edu Spencer Chemistry, Room 315 || Phone Number: (816) 235-2293 Kansas City, Missouri 64110 || FAX Number: (816) 235-1717 =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=