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

From: "Jerome Baudry" <[email-masked]>
Date: Thu, 25 May 2000 09:19:08 -0400

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

[email-masked]
tel: (336) 841-0300 #121 or #120
fax: (336) 841-0310

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From: "Rob Williams" <[email-masked]>
Date: Thu, 25 May 2000 15:39:21 +0100

> Here is the summary of the answers I get: (!!!! ADDITIONAL ANSWERS ARE

Hi Jerome,

Tsar, from Oxford Molecular, has rotatable bond count as an optional
addition to the Lipinski descriptors. The default limit is set to 8.
Tsar also (optionally) ignores amide bonds and bonds connected to 
terminal groups, such as Methyl. Tsar calculates and displays the
descriptors and also produces a column in the spreadsheet of the
number of violations of the limits. 1 violation might be okay, 2
might be unacceptable...

Cheers,
Rob