Drug Discovery

Computational work has contributed to novel drug discovery and design for many years. More details about computer aided drug design and discovery will be coming soon. A project which combines experimental and computation work is as follows.

In collaboration with the Marino group at CARB, I also worked on the discovery of competitive inhibitors of Rev-RRE binding in HIV as a first step toward a new class of therapeutics for AIDS. Our study focused on a portion of HIV-1 RNA genome, so-called Rev Responsive Element (RRE), which interacts with Rev peptide. The association of Rev with RRE is essential for HIV replication, acting as a crucial switch between viral latency and active viral replication. As a consequence, this regulatory protein-RNA interaction represents a potential target for the development of novel inhibitors that might be suitable as therapies for HIV-1 infection.

Despite the promise of RRE as a drug target, only two classes of drug-like ligands that block the RRE-Rev interaction in vitro had been discovered prior to this study.  Using an conceptual approach, my advisor and I selected candidate ligands which seemed to form good interactions with the Rev binding site in RRE. Several of the roughly 20 compounds that I selected for experimental study and tested via fluorescence assays were found to be active. NMR studies of one of these compounds, proflavine, by our  collaborators confirm specific binding at a high affinity site on the RNA molecule. Proflavine and other acridine-derived molecules appear to form a new class of lead compounds for pharmaceutical development towards novel RNA-targeted antiviral drugs.