From chemistry-request -A_T- server.ccl.net Thu May 25 09:22:01 2000 Received: from server.ttpharma.com ([206.74.77.186]) by server.ccl.net (8.8.7/8.8.7) with ESMTP id JAA03169 for ; Thu, 25 May 2000 09:22:00 -0400 Received: from jerome ([192.168.4.24]) by server.ttpharma.com (8.9.3/8.8.7) with SMTP id IAA10234 for ; Thu, 25 May 2000 08:22:41 -0500 From: "Jerome Baudry" To: Subject: SUMMARY: number of rotatable bonds in drug-like molecules: references ? Date: Thu, 25 May 2000 09:19:08 -0400 Message-ID: <001801bfc64b$cfc36840$1804a8c0: at :ttpharma.com> MIME-Version: 1.0 Content-Type: text/plain; charset="iso-8859-1" Content-Transfer-Encoding: 7bit X-Priority: 3 (Normal) X-MSMail-Priority: Normal X-Mailer: Microsoft Outlook CWS, Build 9.0.2416 (9.0.2910.0) Importance: Normal X-MimeOLE: Produced By Microsoft MimeOLE V5.00.2615.200 Thanks very much to all who responded. The paper by Oprea says that 70% of drug-like molecules have between 2 and 8 rotatable bonds. My understanding of the rationale behind this number is that rotation around 8-9 rotatable bonds would cost ~ 9 * 1.4 kj/mol/rotatable bond = 12.6 kJ/mol/rotatable bonds, or ~ 3kcal/mol/rotatable bond. This would be commpensated by a hydrogen bond when the ligand is bound to the receptor. Rotattion around a higher number of rotatable bonds would be more difficult to compensate in term of non-bonded ligand/receptor interactions (?) Commercial softwares include this descriptor as 'drug like'. MOE has a default value of 5 rotatable bonds. MSI' Cerius2 lists the # of rotatable bonds in the same structural subset of the descriptor table than the rule-of-5 descriptors, but does not propose a default value. I don't know about Tripos or OxMol or ... (additional informations welcome). Here is the summary of the answers I get: (!!!! ADDITIONAL ANSWERS ARE WELCOME !!!) ------------------------------------- a good reference is: T. Oprea J. Comp.-Aided Mol. Design 14:251-264 (2000) Property distribution of drug-related chemical matter. According to Opreas analysis, 70% of drug-like compounds have between 2 and 8 rotatable bonds. Hope this helps, Ingo Muegge -------------------------------------- Hi! You might take a look at a recent paper by T. Oprea (Property Distribution in Drug-related database, J. Comput. Aided Mol Des., 2000, 14(3):251-264) where he describes about number of rotatable bonds (RTB) and rigid bonds (RGB), etc. Hope this helps. Asim Debnath --------------------------------------- See Bohm's paper, "The Development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure" Journal of Computer-Aided Molecular Design, Vol 8, p 243-256 (1994) in which he finds a cost of 1.4 kJ/mol/rotatable bond. In a similar vein, see the paper by M. D. Eldridge et. al, "Empirical Scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes" Journal of Computer-Aided Molecular Design, Vol 11 p. 425-445 (1997) where a slightly larger coefficient for a slightly different functional form than Bohm's is found. Kristy Mardis, ------------------------------------------- --------------------------------- Jerome Baudry, Ph.D. Research Scientist, Computational Chemistry TransTech Pharma, Inc. 4170 Mendenhall Oaks Pwky, Suite 110 High Point, NC, 27265 http://www.ttpharma.com jbaudry;at;ttpharma.com tel: (336) 841-0300 #121 or #120 fax: (336) 841-0310