Molecular modeling is a powerful computer-based technology used to identify and design molecules for new medications greatly shortening the discovery phase of drug development. The technique helps determine the relationship between a compounds structure and its biological activity, and offers useful clues about how it might interact with target proteins allowing researchers to focus on the most promising compounds. The major objective of the Laboratory of Molecular Modeling and Drug Design, headed by Asim K. Debnath, Ph.D., is to identify new drugs targeted to the critical sites of HIV-1 life cycle.

One of the major projects of his team is to identify inhibitors of HIV-1 assembly and maturation, especially targeted to the capsid protein. Recently, his team has used structure-based drug design and novel experimental techniques to modify a cell impermeable linear peptide to a cell-penetrating peptide (CPP), which inhibits HIV-1 assembly and maturation. This modified peptide inhibits HIV-1 in cell culture. In addition, his team also identified small molecule inhibitors that target capsid and inhibit HIV-1 assembly and maturation. The laboratory is now engaged in optimizing these lead inhibitors to enhance potency and reduce toxicity. 

Dr. Debnaths group is also actively involved in identifying small molecules aimed at disrupting the binding of the gp120 envelope protein to the T-cell surface receptor CD4 and CCR5, a co-receptor. His group has successfully identified small molecule inhibitors that prevent the binding of gp120 to CD4. The team is now working to optimize the molecules to make them more potent and less likely to cause side effects.

In a collaborative effort with Dr. Shibo Jiang, Head of the Viral Immunology Laboratory, Dr. Debnath works, to identify drug-like compounds as entry/fusion inhibitors targeted to the envelope glycoprotein gp41 of HIV-1. These two labs follow two complementary strategies in their search. Dr. Debnaths team use structure-based drug design techniques to identify promising compounds as hits and Dr. Jiangs group use several screening techniques, developed by his team, to test those compounds for their potential as entry/fusion inhibitors. Together, they have identified several potential lead compounds as HIV-1 entry/fusion inhibitors. The compounds work at the molecular level to prevent the HIV-1 virus from entering and infecting host cells. The team is now working to optimize the molecules for enhancing potency and reducing side effects.