SUMMARY: number of rotatable bonds in drug-like molecules: references ?



 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 !!!)
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 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,
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 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
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