Medicinal Chemistry & Computer Aided Drug Designing and Drug Delivery

Biography

Biography: Victor J. Hruby

Abstract

Most natural ligands for G-Protein Coupled Receptors are peptides, and most of these peptides are linear peptides with multiple conformations in aqueous solution. There are good biological reasons for this, not the least of which is that different conformations are utilized during their biological life. However, they require a specific conformation for their interaction with their membrane bound receptors. Moreover, many of these hormones and neurotransmitters can interact with several receptor subtypes and virtually all native ligands are agonists. For drug design, it often is necessary to design ligands that are highly receptor selective, and often both agonists and antagonists are needed for various medical and biological applications. We have been developing a strategy to deal with the above drug design requirements which includes the following: 1) determining the basic pharmacophore; 2) discovering antagonists; 3) computer assisted homology modeling of receptor ligand interactions for receptor selectivity and agonist vs. antagonist efficacy; 4) conformation constraint by novel cyclization, backbone modification and chi space constraints; 5) monovalent and multivalent ligands depending upon biological and medical application; 6) enhanced bioavailability including blood brain penetration or not. We will illustrate these strategies in the design of ligands for the treatment of prolonged and neuropathic pain, pigmentary disorders, sexual dysfunction and cancer, as time permits.
 

Supported in part by grants from the U.S. Public Health Service and National Institutes of Health