From STEVENSA@CSOVAX.PORTSMOUTH.AC.UK Wed Dec 14 06:21:36 1994 Received: from sun2.nsfnet-relay.ac.uk for STEVENSA@CSOVAX.PORTSMOUTH.AC.UK by www.ccl.net (8.6.9/930601.1506) id GAA12371; Wed, 14 Dec 1994 06:04:53 -0500 Message-Id: <199412141104.GAA12371@www.ccl.net> Via: uk.ac.portsmouth.csovax; Wed, 14 Dec 1994 11:04:14 +0000 Date: Wed, 14 Dec 94 10:54 GMT From: "ADRIAN STEVENS, DEPT. OF CHEMISTRY, UNI. OF PORTSMOUTH" To: CHEMISTRY Subject: Summary of responses for QSAR question. Dear Netters, When I put a question to the next, I promised that I would post a summary of the responses that I recieved. Therefore, as promised, I have included the list below I tried to make a point of replying to everyone who responded, thanking them for the references. However, in case I missed off anyone, then I would just like to say thank you now. Adrian Stevens, University of Portsmouth. PS I hope that everyone has a very happy Xmas/Festivity/Holiday/Whatever! ------------------------------------------------------------------------ Q.S.A.R. Responses... ------------------------------------------------------------------------ From: CBS%UK.AC.NSFNET-RELAY::IT.IRBM::KOEHLER 2-DEC-1994 12:54:16.12 To: stevensa CC: Subj: QSAR Response Dear Adrian: For QSAR's of enzymes, the following would seem a particularly appropriate and recent reference: Nomizu, M.; Iwaki, T.; Yamashita, T.; Inagaki, Y.; Asano, K.; Akamatsu, M.; Fujita, T. Quantitative structure-activity relationship (QSAR) study of elastase substrates and inhibitors. Int. J. Pept. Protein. Res. 1993, 42, 216-226. Abstract: One hundred Suc-X-Y-Ala-pNA peptides: (Suc: succinyl, pNA: p-nitroanilide, X, Y: Gly, Ala, Val, Leu, Ile, Phe, Pro, alpha-aminobutyric acid, norvaline, norleucine) were synthesized and their reaction constants with porcine pancreatic elastase (Km, kcat and kcat/Km) were determined. These reaction constants were quantitatively analyzed using the Free-Wilson/Fujita- Ban method. The contribution of amino acid side chains to the reaction constants Km, kcat and kcat/Km, expressed logarithmically, was found to be additive. On the other hand, 19 elastase inhibitors of the general formula CF3CO-X-Y-Ala-pNA (X,Y: ten amino acids) were synthesized, and their inhibition constants were compared with the Michaelis constant for the corresponding substrates and analyzed using free-energy-related substituent constants. In the analysis of amino acid side chains in the Y position, the Ki value of the inhibitor was generally correlated to the Km value of the substrate, which corresponded to the inhibitor, thus confirming the validity of the equation. log(1/Ki) = 1.271 log(1/Km) + 4.831 This study may serve as a prototypical approach to unraveling structure-activity relationships of peptide substrates and inhibitors of medicinal or agricultural importance. If you are interested in 3D-QSAR and enzymes, check the following references out: (1) DePriest, S. A.; Mayer, D.; Naylor, C. B.; Marshall, G. R. 3D-QSAR of angiotensin-converting enzyme and thermolysin inhibitors: a comparison of CoMFA models based on deduced and experimentally determined active site geometries. J. Am. Chem. Soc. 1993, 115, 5372-84. (2) Motoc, I.; Sit, S. Y.; Harte, W. E.; Balasubramanian, N.; Wright, J. J. 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase: Molecular Modeling, Three-Dimensional structure-activity relationships, inhibitor design. QSAR 1991, 10, 30. (3) Sit, S. Y.; Parker, R. A.; Motoc, I.; Han, W.; Balasubramanian, N.; Catt, J. D.; Brown, P. J.; Harte, W. E.; Thompson, M. D.; Wright, J. J. Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. J. Med. Chem. 1990, 33, 2982-99. (4) Waller, C. L.; McKinney, J. D. Comparative molecular field analysis of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls. J. Med. Chem. 1992, 35, 3660-6. (5) Waller, C. L.; Marshall, G. R. Three-dimensional quantitative structure-activity relationship of angiotensin-converting enzyme and thermolysin inhibitors. II. A Comparison of CoMFA models incorporating molecular orbital fields and desolvation free energies based on active-analog and complementry-receptor-field alignment rules. J. Med. Chem. 1993, 36, 2390-2403. (6) Waller, C. L.; Oprea, T. I.; Giolitti, A.; Marshall, G. R. Three-dimensional QSAR of human immunodeficiency virus (I) protease inhibitors. 1. A CoMFA study employing experimentally-determined alignment rules. J. Med. Chem. 1993, 36, 4152-4160. Ciao, ------------------------------------------------------------------ | Konrad Koehler | Computational Chemistry Group | | internet: koehler@irbm.it | Department of Medicinal Chemistry | | | IRBM | | telephone: +39-6-910-93606 | Via Pontina Km. 30,600 | | fax: +39-6-910-93225 | 00040 Pomezia (Roma) | | | Italy | ------------------------------------------------------------------ -------------------------------------------------------------------------- From: CBS%UK.AC.NSFNET-RELAY::GOV.EPA.HERL.THOR::WALLER 2-DEC-1994 13:20:23.68 To: STEVENSA CC: Subj: Re: CCL:Introductory Q.S.A.R. References.? As a graduate student I found Yvonne Martin's Quantitative Drug Design (Marcel Dekker, New York) an extremely useful introductory text. ******************************************************************** *Chris L. Waller, Ph.D. PHONE 919-541-7976* *Research Chemist FAX 919-541-5394* *waller@thor.herl.epa.gov * *Pharmacokinetics Branch (MD-74) * *ETD/HERL/USEPA * *Research Triangle Park, NC 27711 * * * *Disclaimer: Mention of trade names or products does not constitute* *endorsement by the United States Environmental Protection Agency. * ******************************************************************** --------------------------------------------------------------------------- From: CBS%UK.AC.NSFNET-RELAY::EDU.CWRU.CHEM.CWGK::FERCU 2-DEC-1994 13:30:06.08 To: STEVENSA CC: Subj: QSAR Response Dear Adrian, The most recent book I know of is "QSAR: Hansch analysis and related approaches" by Hugo Kubinyi (VCH: Weinheim, 1993, 240p). It has a good review on the most used QSAR parameters. Besides the well known Hansch analysis, other models are described, such as Free Wilson, pattern recognition techniques, 3D QSAR models (CoMFA). Almost half of the book is dedicated to applications. Over 1000 references. A reduced version of this book can be found in the new edition of "Burger's Medicinal Chemistry and Drug Discovery" (Wolff, M. E., Ed., Wiley: New York, Vol.1, 5th ed., 1994). Regards, Dan Fercu Dan Fercu Computational Chemist Department of Chemistry Case Western Reserve University fercu@cwgk.chem.cwru.edu --------------------------------------------------------------------------- From: CBS%UK.AC.NSFNET-RELAY::COM.ABBOTT.RANDB::CMDA::MARTIN 2-DEC-1994 14:37:14.81 To: STEVENSA CC: Subj: Re: CCL:Introductory Q.S.A.R. References.? The classic book, now out of print but maybe available in your library, is mine: "Quantitative Drug Design", published by Marcel Dekker. There is also a nice introduction in Comprehensive Medicinal Chemistry, Vol 4, edited by Hansch, Sammes, & Taylor. Pergamon. Methods in Enzymology vol 203 edited by Langone also has several interesting chapters. Finally, there is the interesting book edited by Kubinyi "3D QSAR in Drug Design". ESCOM, 1994. Yvonne Martin Abbott Laboratories ---------------------------------------------------------------------------- From: CBS%UK.AC.NSFNET-RELAY::UK.CO.OXMOL::SCOFFIN 5-DEC-1994 08:32:30.54 To: STEVENSA CC: Subj: QSAR Response... Adrian, There are a number of good introductory level texts, depending on what you are looking for; i.e. Hansch Analysis or 3D-QSAR. For the latter I would try '3D QSAR in Drug Design'; H.Kubinyi, ESCOM, 1994. There are good books by Yvonne Martin, Reiner Franke, Han van de Waterbeemd and Mike Tute on various aspects of 2D and 3D QSAR, I can find more specific references if that will help... Good luck in your search, Rob Scoffin =========== Robert Scoffin ________________ QSAR Product Manager | ## ## ## | Oxford Molecular Ltd | ## ## ## | The Magdalen Centre | ## ## ## | Oxford Science Park | ###### | Oxford OX4 4GA | ## | Tel: (0865)784600 | ## | Fax: (0865)784601 | #### | Mobile: (0378) 210813 ---------------- -------------------------------------------------------------------------- From: CBS%UK.AC.NSFNET-RELAY::ORG.ACS::BEP96 5-DEC-1994 14:25:59.89 To: stevensa CC: Subj: QSAR Response Your message was forwarded to me by Nan Butterworth. The following book will be available later this month. Please note that volume I is designed to introduce the reader to QSAR. If you have any specific questions please do not hestitate to email me at bep96@acs.org. Barbara Pralle Acquisitions Editor TWO VOLUME SET "BOOK TITLE (Vol. 1):" Exploring QSAR "SUBTITLE:" Fundamentals and Applications in Chemistry and Biology AUTHORS(S): Corwin Hansch and Albert Leo "BOOK TITLE (Vol. 2):" Exploring QSAR "SUBTITLE:" Hydrophobic, Electronic, and Steric Constants AUTHORS(S): Corwin Hansch, Albert Leo, David Hoekman ISBN: 0-8412-2993-7 PRICE: $99.95 PUBLICATION DATE: December 1994 SIZE: 7 X 10 inches (Vol. 1) 8 1/2 X 11 inces (Vol. 2) BINDING: Clothbound (Vol. 1) Clothbound (Vol. 2) ESTIMATED PAGES: 900 AUDIENCE/LEVEL: Medicinal chemists, agrochemical chemists, toxicologists, environmental scientists, computational chemists, pharmaceutical scientists, scientists involved in computer-assisted drug discovery, bioorganic chemists, pesticide chemists and formulators, analytical chemists working with partition coefficient measurements. HIGHLIGHTS: Investigates the interaction of organic compounds with various forms of life including macromolecules, enzymes, organelles, etc. Introduces the Hammett equation and its applications. Discusses the design of bioactive compounds. Includes extensive tables of approximately 17,000 partition coefficients from octanol/water as well as a comprehensive listing of electronic and steric parameters used in the design and study of bioactive organic compounds. ----------------------------------------------------------------------------- End of list -----------------------------------------------------------------------------