Subject: Quantative prediction of binding affinities

From: Arthur Wang <[email-masked]>
Date: Mon, 15 Apr 1996 20:44:37 -0700 (PDT)

Dear Netters,

In structure-based drug design, maybe the real problem lies in scoring the
candidates, i.e. predicting the binding affinities to find the promising
ones among the potential ligands. Obviously if the score relates directly
to the free energy changes upon the binding process, designers will be
lent much convenience. 

Many approaches have focused on this problem. Some use rule-based energy
functions (e.g. J.Comp.-Aided Molecular Design, 1994, 8, 243-256), some
use force field to evaluate the energies (e.g. GRID, DOCK, & J.Comp.Chem.,
1995, 16, 454-464). For some reasons, we prefer force field method. (Any
comments on the comparison of these two methods are welcome! :-) In such a
energy function, these terms are usually included: 

E = E(vdW) + E(electrostatic) + E(desolvation) + E(H-bond) + ...

Different force fields often have different forms. So here comes my
question: Are there anyone who has checked the validities of these force
fields? Which one is more reasonable and which is less reasonable? Usually
a few crystal structures of complex are rebuilt by using a specific
method, but so far I have not seen any attempts to predict quantitatively
the experimentally determined binding constants or free energy changes. 
This is critical. Because we will probably yield nothing valuable by 
using a false energy estimation. 

Any comments? Any clues? I would like to calculate the binding energies
for a series of complexes by using current force fields. In this case, I
need a list of complex PDB entries which have reliable determined binding
constants. Anyone maintains such a list? 

Answers will be summaried. Thanks in advance.

Arthur

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_/   Arthur Wang                     Doctoral Candidate     _/
_/   Molecular Design Lab                                   _/
_/   Institute of Physical Chemistry, Peking University     _/
_/   Beijing 100871, P.R.China                              _/
_/                                                          _/ 
_/   E-mail: [email-masked]                          _/
_/   Tel: 86-10-2751490    Fax: 86-10-2751725               _/
_/   WWW: http://www.ipc.pku.edu.cn/moldes/arthur/home.html _/
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