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COMPUTATIONAL STRUCTURAL PROTEOMICS AND RATIONAL DRUG DESIGN
RUBEN ABAGYAN
Department of Molecular Biology
The Scripps Research Institute
Founder, Molsoft, LLC
ABSTRACT:
Large-scale discovery of new human genes, gene families and isozymes creates an exciting biomedical opportunity.
The sequence-structure gap is rapidly increasing despite the efforts of the companies and centers for high-throughput
structural proteomics.
However, advanced modeling by homology techniques can be employed to generate 3D models for most of the
interesting new gene family members. This opens many new opportunities for structural structure based functional
annotation and molecular design.
First, we have developed two new techniques to assist rational drug design using crystallographic structures or
models by homology. The binding pockets can be automatically identified even if the native ligand is unknown. This
algorithm has been tested on over 10,000 complexes. We have also built a comprehensive database of protein
pockets and clustered them into families.
Second, a deformed ligand binding pocket in a model by homology can be refined by explicit global optimization of
one or several known ligands and surrounding receptor side-chains.
Third, a procedure is described to identify a native ligand from a collection of all known biological substrates. The
procedure was also applied to some receptors including GPCRs.
Finally, new computational technology for virtual ligand screening allows us to generate alternative receptor
conformations and perform flexible docking of hundreds of thousands of virtual compounds to the binding site. The
success of this technology is demonstrated on several benchmarks and in six experimental projects, which tested the
prediction results. For well-defined binding pockets only about 1% of the initial compound set actually needs to be
synthesized and tested. Using ICM docking and scoring technology we have identified new ligands in a number of
cases, including cases in which a model was used instead of a crystallographic structure and a case in which proteinprotein interaction has been targeted.
Some of the recent results tested experimentally include: the de novo design of novel antagonists of thyroid hormone
receptor, for which no antagonists were known before and, consequently, no antagonist-bound structure was known;
de novo design of ligands targeting Ephrin-Ephrin receptor interactions.
Friday, September 20, 2002
11:00 a.m. – 1:00 p.m.
(Talk starts at 11:15)
Building 4, Room 231
Professor Abagyan's invitation is possible because of the
generous support of Genome Therapeutics Corporation,
with special thanks to Dr. Keith Weinstock.
Massachusetts Institute of Technology
Department of Mathematics
Cambridge, MA 02139