Randy J. Zauhar MS, PhD
Randy J. Zauhar MS, PhD
Director, Graduate Program in Bioinformatics
Professor of Chemistry and Biochemistry
Associate Professor of Bioinformatics
Research Associate Professor of Biophysics
BS (Eastern Washington)
BA (Eastern Washington)
MS (Penn State University)
PhD (Penn State University)
- Computational chemistry
- Computer-aided drug design
Using shape signatures to compactly represent the shape of drug molecules and the protein receptor sites for computer-aided drug design. Applying shape signatures toward developing new COX-2 inhibitors, estrogenic compounds, and opiods. Development of methods of computer-aided drug design, with applications involving a variety of biological targets. Development of computational techniques to estimate electrostatic and solvation effects in biomolecular systems.
My current research efforts are focussed on the problem of designing drug molecules (inhibitors) against highly mutable targets such as HIV protease. As part of an NIH-funded collaboration with industrial and academic partners, I have been developing a computer-based drug design system called ALMS (Analysis of Ligand binding with Multiple Substitutions). ALMS works by attaching user-defined selections of chemical fragments to selected sites on a pre-existing "framework" compound, and rapidly orienting the attached fragments in the binding site of a target protein using a genetic algorithm. ALMS works "combinatorially," in that it builds all possible combinations of selected fragments at framework sites, and can easily generate many thousands of compounds.
The drug compounds thus generated can be "screened" by evaluating the interaction energy between each inhibitor and the protein binding site. This is done using a molecular mechanics potential energy function. Compounds with lower (more negative) interaction energy are predicted to be better binders, more effective inhibitors, and better candidates for synthesis and testing. Using ALMS it is also possible to correlate observed biological activity with energy, and to construct models that directly predict measured drug efficacy.
We are also working on the important question of including the effects of solvation in estimates of drug binding energy. This is being done using continuum models that I have developed, which take into account the charge distribution of the solute and the geometry of the molecular surface to predict the effects of polarized solvent. This technique is now being integrated with ALMS.
Shape signatures is a novel technique for computer-aided drug design developed over the last few years by USP associate professor of biochemistry Randy Zauhar and collaborators. It is a system for compactly representing the shape of drug molecules and the protein receptor sites they target. It was recognized by Emil Fischer in the nineteenth century that the molecules central to the processes of life must recognize each other by a mechanism similar to a key fitting into a lock, and we now recognize that his “lock and key hypothesis” is as central to understanding the mechanics of life as Darwin’s ideas are to understanding evolution and development. The central
idea is complementarity, that bioactive molecules (including metabolites, hormones, and drugs) fit into protein receptors that provide a pocket of the right size and shape to accommodate the small molecule, much like a three-dimensional puzzle. This suggests two routes to identifying new drugs—find molecules similar in shape to a known active or complementary in shape to a known receptor. The shape signatures approach works with either of the two routes just mentioned. The method uses a technique much like ray-tracing to explore the shape of a drug molecule or, alternatively, the shape of a protein receptor pocket. Compact descriptors of shape are generated from the ray-trace, and they can be easily and quickly compared, leading to the capability of rapidly scanning very large chemical libraries for candidate drug molecules.
The method is easily extended to search for other quantities in combination with shape, for example, molecular polarity. Shape signatures is being applied in a number of projects aimed at developing new therapeutics, including COX-2 inhibitors, new estrogenic
compounds, and new opioids.
Selected Scholarly Activity
“Enrichment of Ligands for the Serotonin Receptor Using the Shape Signatures Approach,” K. Nagarajan, R. Zauhar, and W. J. Welsh, J. Chem.Inform. and Mod., 2005, 45, 49.
“Shape signatures: A new approach to computer-aided ligand- and receptorbased drug design,” R. J. Zauhar, G. Moyna, L. F. Tian, Z. J. Li, and W. J. Welsh, J. Med. Chem., 2003, 46, 5674.
“Derivation of C-13 chemical shift surfaces for the anomeric carbons of oligosaccharides and glycopeptides using ab initio methodology,” C. W. Swalina, R. J. Zauhar, M. J. DeGrazia, and G. Moyna, J. Biomol. NMR, 2001, 21, 49.
“Evidence for a strong sulfur-aromatic interaction derived from crystallographic data,” R. J. Zauhar, C. L. Colbert, R. S. Morgan, and W. Welsh, Biopolymers, 2000, 53, 233.
“A fast and space-efficient boundary element method for computing electrostatic and hydration effects in large molecules,” R. J. Zauhar and A. Varnek, J. Comp. Chem., 1996, 17, 864.
|Office location:||McNeil Science and Technology Center Room 222|
|Mailing address:||Box 48|
University of Sciences
600 South 43rd Street
Philadelphia, PA 19104-4495
r [dot] zauhar [at] usciences [dot] edu