From owner-molreps@hgmp.mrc.ac.uk Tue May 2 10:15:32 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id 2054217AC3; Tue, 2 May 2000 10:15:32 +0100 (BST) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 1) id 9577617AB1; Tue, 2 May 2000 10:15:29 +0100 (BST) To: molreps@net.bio.net Newsgroups: bionet.molecules.repertoires From: Steve Heller Subject: ChemInt2000 - Poster Submission Date: 28 Apr 2000 12:21:49 +0100 Organization: BIOSCI/MRC Human Genome Mapping Project Resource Centre Message-ID: Sender: owner-molreps@hgmp.mrc.ac.uk Precedence: bulk This is just a short note to remind eveyone that the web Abstract Submission deadline for papers to be considered for ChemInt2000 oral presentations is June 1, 2000. The web submission form is operational for the Chemistry and the Internet (ChemInt2000) meeting being held in at Georgetown University in Washington DC on September 23-26, 2000. The draft program of invited speakers, workshops, markup langauge tutorial, and panel sessions is available on the meeting web site: http://www.chemint.org You are urged to look at the program and to consider submitting a poster paper to the meeting. Some 8-10 of poster papers will be selected for oral presentation at the meeting. The main lecturers for the meeting will be: Rene DePlanque, FIZ - Berlin Jim Myers, Pacific Northwest Labs Glen Hopkinson, Synopsys Scientific Systems Wolf-Dietrich Ihlenfeldt, University of Erlangen-Nurenberg Jim Ostell, NIH/NLM/NCBI Engelbert Zass, ETH Henry Rzepa, Imperial College, London Peter Murray-Rust, Nottingham University Technical Sponsors are: ACS CINF Division ACS COMP Division The Chemical Structure Association (CSA) Georgetown University - Department of Chemistry Special Libraries Association (SLA) Chemistry Division Royal Society of Chemistry (RSC) Steve Heller Steve Heller, Guest Researcher NIST/SRD, Mail Stop: 820/113 820 Diamond Avenue, Room 101 Gaithersburg, MD 20899-2310 USA E-mail: chem@feldmann.nist.gov --- From owner-molreps@hgmp.mrc.ac.uk Tue May 2 14:02:47 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id 6434C17B1E; Tue, 2 May 2000 14:02:47 +0100 (BST) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 1) id 9D7D117A94; Tue, 2 May 2000 14:02:45 +0100 (BST) To: molreps@net.bio.net Newsgroups: bionet.molecules.repertoires From: Shu-Kun Lin Subject: Rule of 5 Date: 2 May 2000 10:19:19 +0100 Organization: BIOSCI/MRC Human Genome Mapping Project Resource Centre Message-ID: <38FC2665.4410A024@mdpi.org> Sender: owner-molreps@hgmp.mrc.ac.uk Precedence: bulk Hi, If you have contact e-mail or address of Dr. Lipinski please let me know. Thanks! He is the author of The Rule of Five: (http://pubs.acs.org/hotartcl/mdd/99/janfeb/rule.html) An awareness tool for discovery chemists: Compounds with two or more of the following characteristics are flagged as likely to have poor oral absorption. More than 5 H-bond donors Molecular weight >500 c log P>5 Sum of N's and O's (a rough measure of H-bond acceptors) > 10 Reference: Lipinski, C. A. Presented at the Fourth International Conference on Drug Absorption, Edinburgh, Scotland, June 1997. -- Dr. Shu-Kun Lin Molecular Diversity Preservation International (MDPI) Saengergasse 25, CH-4054 Basel, Switzerland Tel. +41 79 322 3379, Fax +41 61 302 8918 E-mail: lin@mdpi.org http://www.mdpi.org/lin/ --- From owner-molreps@hgmp.mrc.ac.uk Tue May 2 14:04:53 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id 5D48117B27; Tue, 2 May 2000 14:04:53 +0100 (BST) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 1) id D64AB17B1E; Tue, 2 May 2000 14:04:51 +0100 (BST) To: molreps@net.bio.net Newsgroups: bionet.molecules.repertoires From: Steve Heller Subject: Chemistry Search Engine web site Date: 2 May 2000 10:18:16 +0100 Organization: BIOSCI/MRC Human Genome Mapping Project Resource Centre Message-ID: Sender: owner-molreps@hgmp.mrc.ac.uk Precedence: bulk There is a new and free chemistry web site, with over 15,000 different url's of chemistry web sites - www.chemindustry.com This web site is trying to become the Yahoo of chemistry. Steve --- From owner-molreps@hgmp.mrc.ac.uk Tue May 2 14:08:37 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id D80D417B2C; Tue, 2 May 2000 14:08:36 +0100 (BST) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 1) id 2FA4917B18; Tue, 2 May 2000 14:08:34 +0100 (BST) To: molreps@net.bio.net Newsgroups: bionet.molecules.repertoires From: Shu-Kun Lin Subject: Invitation: Compounds stability Date: 2 May 2000 10:13:29 +0100 Organization: BIOSCI/MRC Human Genome Mapping Project Resource Centre Message-ID: <390986E6.6F06F78A@mdpi.org> Sender: owner-molreps@hgmp.mrc.ac.uk Precedence: bulk Hi, Any one who did research regarding the stability of chemical samples stability during storage under different conditions (under light, in DMSO solution, at RT, etc.), please contribute a report for publication in MOLECULES (http://www.mdpi.org/molecules). Shu-Kun Lin -- Dr. Shu-Kun Lin Molecular Diversity Preservation International (MDPI) Saengergasse 25, CH-4054 Basel, Switzerland Tel. +41 79 322 3379, Fax +41 61 302 8918 E-mail: lin@mdpi.org http://www.mdpi.org/lin/ --- From owner-molreps@hgmp.mrc.ac.uk Wed May 10 08:49:45 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id D08ED17B08; Wed, 10 May 2000 08:49:43 +0100 (BST) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 1) id 2E48B17A77; Wed, 10 May 2000 08:49:41 +0100 (BST) To: molreps@net.bio.net Newsgroups: bionet.molecules.repertoires From: Bob Snyder Subject: Use of Toxicological Information in Drug Design Date: 10 May 2000 08:38:32 +0100 Organization: BIOSCI/MRC Human Genome Mapping Project Resource Centre Message-ID: <8E13FBBA26A9DA119ED400A0C9AB2CE50451F82C@shepherd.mdli.com> Sender: owner-molreps@hgmp.mrc.ac.uk Precedence: bulk I would like to draw to your attention a session on the "Use of Toxicological Information in Drug Design" at the upcoming ACS in Washington DC (August 20-24, 2000). The session is being organized by the Chemical Information (CINF) division. Below are the abstracts for the session, beginning with the keynote address by Dr. Joseph Contrera, associate director of the Office of Testing and Research at the FDA. I hope to see you there. Bob Snyder ------------------------------------- 1. Keynote Address: "Application of toxicology databases in drug development" by Joseph F. Contrera and Edwin J. Matthews (FDA's Office of Testing and Research) In drug development, the application of combinatorial chemistry and high through put screening of compounds has resulted in an unprecedented increase in the number of compounds identified with potentially desirable pharmacological properties. The selection of lead compounds is currently hampered by limitations in the available methods for assessing toxicity. CDER files are a unique repository of the results of clinical and non-clinical toxicology studies. With the major advances in computer and information technology this unique scientific resource can be more effectively used to improve the scientific basis of regulatory decisions and product development. A current challenge is developing means to identify useful relationships and insights from large datasets. Under a cooperative research and development agreement (CRADA), the FDA CDER modified and enhanced the capability of Multicase computational toxicology software to predict the carcinogenic potential of molecules based on chemical structure. Such software has potential regulatory and drug development applications that can ultimately benefit the public health. 2. "Computational toxicology and virtual development in drug design" by Dale E. Johnson and Grushenka H. I. Wolfgang (ddplatform LLC) The attrition rate of lead compounds that are optimized to development candidates and that eventually reach early clinical trials is still alarmingly high. One key reason for the high failure rate is undesired or unpredicted toxicity - either in animals or humans. Currently, a wide array of predictive tools is being developed with the goal of improving lead compound selection at the earliest stage. These new in silico approaches are changing toxicology into a knowledge- and information-based science where structure-toxicity-relationships are beginning to be elucidated. Predicting potential toxicity requires knowledge of both ADME and pharmacokinetic data across species as well as an understanding of mechanisms of action and the chemical species that elicits the initial toxic event. Although the toxicity "bottleneck" is formidable, virtual approaches using simulation algorithms are expected to accelerate and increase the success of early drug development within the next 3-5 years. 3. "The paradigm shift from traditional to virtual" by Stephen K Durham (Bristol-Myers Squibb) The intensely competitive global pharmaceutical business environment has forced the need for the early and successful selection of viable drug candidates, and the abandonment of the traditional development paradigm. The enormous drug developmental costs necessitate the identification of toxicologic liabilities of novel compounds during the initial and least expensive phase of the discovery process. The incorporation of in silico programs to predict toxicity, accompanied by aggressive model development, will be fruitful avenues worth pursuit in the drug candidate evaluation algorithm. 4. "Application of Computational Toxicology (ComTox) and Multicase (MCASE) Software to the FDA Mission" by Edwin J. Matthews and Joseph F. Contrera (FDA's Office of Testing and Research) Under a CRADA between FDA and Multicase, Inc., new ComTox software programs have been developed that estimate chemical-toxic responses and dosages in animals using animal toxicology studies, and in humans using pre-market clinical-trial data and post-market adverse-event data for pharmaceuticals. This talk will examine two software modules that predict the potential carcinogenicity, and the maximum-tolerated-dose (MTD), in rats and mice, and it will elaborate on the experimental parameters that were accounted for the program's high predictive performance and excellent coverage for FDA-regulated substances. The parameters include: (1) large control data sets (n>1000), (2) separate modules for each study cell (rat & mouse), (3) the use of biological potency scales, and (4) a human expert system. The talk will also review the current and future regulatory applications of ComTox within the Agency. 5. "Data mining of toxic chemicals and database-based toxicity prediction" by Jiansuo Wang and Luhua Lai (Peking University) In the early stage of drug discovery, especially for computer-aided drug design, a large number of molecules will be proposed as potential leads and the bioactivity risk of these molecules is expected to be evaluated prior to synthesis. The rule-based expert systems have been used for the aim, while mining of a large amount of toxicological data can provide us with another promise. In term of pharmacologists/toxicologists, toxicants are the drugs that cause vital harm. Therefore, the biochemical basis of toxic chemicals is the same as that of drugs and there exist toxicant-receptor systems just like drug-receptor systems. Under such a notion, we introduce some concepts and technologies, which are developed in drug design, into toxic chemicals, and conduct the following work.. I. We have studied the structural features of toxic chemicals from the RTECS database associating with specific toxicity. Potential active frameworks, groups and structure patterns for specific toxicity are obtained by computational chemistry approaches. These structural features of toxic chemicals will be helpful to understand activities of toxic chemicals and useful to predict toxicity of chemicals, especially in the early stage of drug design. II. We take a two-step strategy to explore noncongeneric toxic chemicals from the database RTECS: the screening of structure patterns and the generation of detailed relationship between structure and activity. From the performance of overall procedure, such a stepwise scheme is demonstrated to be feasible and effective to mine a database of toxic chemicals. III. We develop one program as database-based toxicity predictor of chemicals (dbToxPre). For one activity-query molecule, the program firstly retrieves its structure-related molecule set by quick shape comparison with the molecules in toxicological database; then carries out detailed structure-toxicity-relation analysis to the molecule set and produce the toxicity prediction of the query molecule. The program mainly includes four parts: a) a fast and efficient clustering of molecules based on molecular shape, b) field-based similarity computation of molecular structure based on shape cluster, c) flexible CoMFA analysis of molecules based on shape cluster, and d) a database of toxic chemicals suitable for such procedure. 6. "In Silico Toxicology Screening of Estrogenic Compounds as Potential Therapeutic Agents" by William J. Welsh (University of Missouri-St. Louis) Specific estrogen-like compounds known as Selective Estrogen Receptor Modulators (SERMs) have attracted tremendous interest in the pharmaceutical industry and elsewhere as potential therapeutic agents for myriad applications in medicine. We have employed an integrated array of ligand-based and receptor-based approaches to design a large number of estrogen agonists and antagonists spanning several chemical classes. As part of this drug discovery program, we have developed and applied various in silico strategies for rapid screening of these compounds in terms of their toxicological and environmental effects. My talk will discuss growing concerns about the possible environmental impact of estrogenic compounds. It will also describe our computer-based models for predicting the biological activity and toxicological profile for the novel set of compounds under development in this laboratory. ------------------------------------- Robert W. Snyder, Ph.D. Director, Chemistry Marketing MDL Information Systems email: bobs@mdli.com telephone: 510-357-2222 Never stop searching. --- From owner-molreps@hgmp.mrc.ac.uk Wed May 10 13:49:53 2000 Return-Path: Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 110) id C299017B66; Wed, 10 May 2000 13:49:52 +0100 (BST) Received: by mercury.hgmp.mrc.ac.uk (Postfix, from userid 1) id B7C2D17A4E; Wed, 10 May 2000 13:49:50 +0100 (BST) To: molreps@net.bio.net Newsgroups: bionet.molecules.repertoires From: Nigel.Kenward@nottingham.ac.uk (Nigel Kenward) Subject: Phagemid rescue Date: 10 May 2000 12:24:27 +0100 Organization: BIOSCI/MRC Human Genome Mapping Project Resource Centre Message-ID: <39194551.8AB69BC9@nottingham.ac.uk> Sender: owner-molreps@hgmp.mrc.ac.uk Precedence: bulk I am using the Pharmacia Recombinant Phage Antibody System to attempt to produce a "library" using a monoclonal scFv specifically amplified by PCR. Having successfully ligated the scFv into the vector (and tested using colony PCR), I can then culture isolated colonies, but when I add the helper phage M13K07 the cells either appear to die or the concentration of phage produced is negligable. Has anyone else had such problems or does anyone have any suggestions where I could be going wrong? ---