Talk abstract:
Application of the GrowMol Computer Program to the Aspartic
Acid Pepsin: Results of the Design and Synthesis of a Novel
Inhibitor
Regine Bohacek, Ariad Pharmaceuticals
The conceptual basis for structure-based drug design was formulated
100 years ago by Emil Fisher. His "lock and key" hypothesis
is a constantly recurring theme in modern drug design. Previously,
knowledge of the "lock", i.e. the biochemical target, could
only be inferred by the structures of a variety of "keys" (ligands)
all of which fit the "lock". However, now, thanks to the advances
in protein expression, X-ray crystallography and NMR, more and
more often we now actually have the 3-dimensional structure
of the "lock". And, thus, the new challenge is how to utilize
this information to rapidly discover novel, potent molecules
which will exquisitely fit the "lock".
A number of computational methods are emerging that can use
these 3-dimensional structures to design, de novo, molecular
structures able to bind with high affinity to a target. We are
developing a computer program called GrowMol, which generates
organic structures that are both spatially and chemically complementary
to the target binding site. By "growing" molecules an atom at
a time to fill the various nooks and crannies of a binding site,
GrowMol can generate structures with exquisite complementary
to the host. At each step, the position and type of atom to
be added are randomly selected using Boltzmann statistics to
bias acceptance toward atoms that can form favorable interactions
with the binding site. Previous work has demonstrated that GrowMol
could generate known inhibitors of thermolysin as well as large
number of novel, diverse structures complementary to the thermolysin
binding site [1]. We will describe the results of applying GrowMol
to aspartic acid pepsin and the discovery of a novel, low molecular
weight inhibitor.
Another exciting area of drug design is that of combinatorial
chemistry. If the structure of the target is known, then both
the scaffold and the building blocks can be "screened" on the
computer prior to synthesis. Knowledge of which of the typically
thousands of available building blocks may form the most favorable
interactions with the binding site, can improve the probability
of finding "hits"! Examples of the use of GrowMol for designing
libraries will be described.
This is joint work with Colin McMartin, Peter Glunz and Daniel
H. Rich.
Reference
- Bohacek, R. S., McMartin, C., SIAM J. Math Anal.
1995, 116, 147--179.
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Schedule
1996-1997
Mathematics in High Performance Computing
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