Automated Site-Directed Drug Design Using Molecular Lattices
R. Lewis, D. Roe, C. Huang, T. Ferrin, R. Langridge, and I. Kuntz
Department of Pharmaceutical Chemistry
University of California
San Francisco, CA 94143-0446
ABSTRACT
Receptor-based drug design is predicated on the knowledge
of the structure of a target receptor and the principles of
molecule recognition. The objective is to produce a wide
diversity of structures that are sterically and electrostatically
complementary to a specified receptor site. Many
drug-receptor interactions are controlled by a few key
receptor groups. This observation leads to a design approach
in which one focuses on chemical fragments that putatively
interact with the key receptor groups. There then remains
the difficult task of joining the fragments into molecular
structures that match the spatial patterns of recognition
forces in the receptor site. In this paper, we describe a new
modeling program, BUILDER, that combines database
searching techniques and structure generation algorithms
within an interactive graphics modeling environment
(MidasPlus). A novel tool for process communications (delegate)
is introduced and examples of its use are given. To
demonstrate the functionality of the package and its ability
to produce novel structures, we examine the active site of
HIV-1 protease.
tef@cgl.ucsf.edu / July 1991