Subject: Re: CCL:Flexible docking software

From: [email-masked] (Mark C. Surles)
Date: Wed, 13 Sep 1995 12:21:57 -0800

>   It seems that many of the molecular docking packages only handle rigid
>molecules.  Anyone knows of any packages (public-domain or commerical or
>yet-to-be-released-versions) that perform 'flexible' docking?
>   Thanks.
>
>best regards - teck-sin

Sculpt from Interactive Simulations provides both flexible receptor and
ligand during real-time, user-guided docking.  Flexibility is a function of
energy minimization.

See the Flavin/Flavodoxin, HIV protease, and Beta lactamase examples in the
demos.  Demos are available via the WWW at http://www.intsim.com/~isigen or
send email to [email-masked].

Mark Surles

Interactive Simulations, Inc.      Phone: (619) 658-9462
5330 Carroll Canyon Road           FAX:   (619) 658-9463
Suite 203                          Email: [email-masked]
San Diego, CA  92121               URL:   http://www.intsim.com/~isigen

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From: [email-masked] (Nick Hodge)
Date: Wed, 13 Sep 1995 18:12:49 -0400

A brief expansion on Congxin's note regarding flexible docking (appended
below):

As indicated, the method was developed at DuPont Merck and employs
molecular dynamics to 'fly' a ligand into the active site of an enzyme. The
active site is flexible and represented explicitly, an intermediate region
of the enzyme is restrained, and a grid represents the rest of the enzyme.
An atom-based solvation term is added (Stouten et al. Mol. Simulations, 10,
97, 1993). The initial implementation (Luty et al., JCC, 16, 454, 1995) was
able to reproduce the crystallographic orientation of benzamidine in
trypsin rapidly and accurately, starting from random orientations outside
of the active site; similarly, leucine hydroxamic acid finds its way into
the crystallographically observed orientation in thermolysin (Wasserman and
Hodge, Proteins: Structure, Function and Genetics, in press).

In neither case do we attempt to correlate energies with the experimentally
observed conformations, but preliminary analysis suggests that some
correlation is possible. The successful extension to thermolysin and a more
flexible inhibitor is also encouraging. However, the method has to be
considered preliminary and in need of extensive testing and improvement.

The Biosym implementation includes a Monte Carlo conformation/location
generator and minimization to find optimum docked sites, as well the
Discover 3.0 environment and cvff or cff91 forcefields; Amber is still
being used as well at DuPont Merck. The results with cvff are similar,
although not identical, to Amber in the limited comparisons that have been
run.

We are very interested in comments, suggestions, enhancements etc. to the
method. We should also make clear that it is an extension of earlier and
continuing docking protocols of Goodford, Olson, Kuntz, Bohm etc. and
relies on many of their observations and ideas.

                    Nick Hodge
                    DuPont Merck

At 3:55 AM 9/13/95, Congxin Liang ([email-masked]) wrote:

>On Mon Sep 11 12:12:52 1995, Lim Teck Sin wrote:
>
>In the 950 release from Biosym/MSI scheduled for next month,
>there is a new product named Affinity which does flexible docking.
>Both the ligand and receptor are flexible. It is an energy-based
>method and it combines the merits of Monte Carlo, minimization and dyanmics.
>It also uses the molecular mechanics/grid method of Luty et al.
>(JCC, 16, 454, 1995) to speed up the calculation and to include
>an implicit solvation model of Stouten et al. (Mol. Simulations,
>10, 97, 1993). For more infomation, please contact your local
>Biosym/MSI sales office.
>
>Congxin Liang
>Biosym/MSI

--
C. Nick Hodge, Ph.D.
Head, Computer Aided Drug Design Group
The DuPont Merck Pharmaceutical Company
P.O. Box 80353, Wilmington, DE 19880-0353
Phone: +1 (302) 695 3698
Fax: +1 (302) 695 2813
Internet: [email-masked]
Please note the new address (chemsci5) as chemsci1
will not work after August 7th.