Subject: Summary: Quantitative prediction of binding affinities

From: Arthur Wang <[email-masked]>
Date: Sun, 21 Apr 1996 20:29:00 -0700 (PDT)

Dear CCLers,

Last week I posted the question about prediction of binding affinities. 
Several answers have come into my mailbox. They are proved to be very 
helpful. I thank all of these concerns and the summary is here.

My original question is: 
---------------------------------------------------------------------------
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? 
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ANSWERS:
From: "Dr. Chris L. Waller" <[email-masked]>

A group of us in Garland Marshall's lab at Washington University were
very interested in this particular problem. To this end we developed
a "force field" which was designed to predict the Ki's for untested
compounds. To my knowledge, this manuscript is in press in JACS. Look
for a manuscript entitled "VALIDATE" by Head, et al.

From: [email-masked] (Xinjun Hou)

>Are there anyone who has checked the validities of these force
>fields?

  We asked similar question a few years back. One motivation was
  to find a relative efficient method to predict binding energy, which
  can be used in our daily drug design project. Based on our own
  ligand-protein cocrystal structure databases, we found that a generic
  force field could give reasonable relative binding energy for cogeneric
  series of ligands. Some sort of solvation model is needed to obtain
  better correlation. 

>...but so far I have not seen any attempts to predict quantitatively
>the experimentally determined binding constants or free energy changes. 

  No really correct, a good review can be found in 
  Ajay and M. A. Murcko, J. Med. Chem. 1995, V38:N26:P4953

>...I need a list of complex PDB entries which have reliable determined
>binding constants.

 Check out a publication from G. R. Marshall's group (could not
 find the reference, might be ref#80 in Ajay's paper)

From: "W. Todd Wipke" <[email-masked]>

There are many examples showing that one can not predict the binding affinity
with molecular mechanics by only considering the substrate in the protein
cavity.  It is only part of the story.
-Todd Wipke

From: [email-masked]

Dear Arthur; I read your post in the CCL, it is realy frastrating as I
met it few years ago. There are many force fields for the energy calculation
in drug design, predicting protein and DNA, no people know which one
is best or worst, the choice of the force field is subject to your
own purpose. Try the force fields in your calculation to see which
one is the best to fit your problem. In protein/DNA prediction, there
are three force fields are commonly used, ECEPP/2 which was developed
by Sheraga etc, Amber and Opls, also a combination of the AMBER/OPLS
in Macromodel package is good for the prediction of the proteins.

From: [email-masked]

Dear Arthur --

> 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. 

There have been a few studies comparing molecular mechanics force fields
in terms of how well they reproduce experimentally determined geometries
and rotational energy barriers but I am not aware of any studies attempting
to validate standard molecular mechanics force fields for the purpose of
calculating *inter*molecular interaction energies.  Since the force fields
were not developed for this purpose and were not parameterized for this
purpose, they will not be particularly accurate when used for this purpose.

I'm glad to see that you  included E(desolvation) in your model.  Actually,
as you probably know, it should be Delta-G(desolvation).  Have you also
thought about the need to address the loss of conformational entropy which
occurs as ligands with rotatable bonds become "locked" within the receptor?
Also, don't forget to consider the change in conformational energy which
occurs as the ligand distorts from its preferred conformation in solution
to the conformation imposed by the receptor.  Since you will have a difficult
time guessing the exact conformation imposed by the receptor, there will be
considerable error associated with this contribution!  Perhaps so much that
other errors don't seem so important.  Perhaps so much that the notion of a
scoring function becomes less "exciting."

  -- Bob Pearlman

From: "Alexander Hillisch" <[email-masked]>

Have a look at:

J.Med. Chem. (1995) 38, 305-317

People form Merck describe molecular mechanics calculations with they modified
MM2 force field to predict activities of HIV-PR-inhibitors.
I would be interested in other responses to your question to CCL. I am doing
similar things so I would like to please you for closer contact with me.

Regards,

Arthur

_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/
_/   Arthur Wang                     Doctoral Candidate     _/
_/   Molecular Design Lab                                   _/
_/   Institute of Physical Chemistry, Peking University     _/
_/   Beijing 100871, P.R.China                              _/
_/                                                          _/ 
_/   E-mail: [email-masked]                          _/
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