Growmol, A De novo Computer Program, and its Application to Thermolysin and Pepsin: Results of the Design and Synthesis of a Novel Inhibitor

Abstract

The conceptual basis for structure-based drug design was formulated 100 years ago by Emil Fisher(1). 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, thanks to the advances in protein expression, X-ray crystallography and NMR, more and more often we now actually have the three dimensional structure of the biological target. 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 which is use three dimensional structures to automatically design, de novo , molecules which fit into binding sites. We describe here the development and use of a computer program called GrowMol(2, 3), 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. GrowMol was first tested with thermolysin. The program generated known inhibitors as well as large numbers of novel, diverse structures complementary to the thermolysin binding site. Recently, GrowMol was applied to the aspartic acid protease, pepsin, resulting in the discovery of a novel, low molecular weight inhibitor. (4)