Computer-aided protein structure studies: Hunting down the hidden secrets of HIV

Computer simulations provide a powerful tool for studying a protein's structure/function relationships at atomic resolution, and these techniques were applied to important drug targets from the Human Immunodeficiency Virus (HIV). To elucidate the regions where the viral and genomic DNA interact with the catalytic subunit of HIV integrase, dinucleotides were docked to its surface. Molecular Dynamics studies were employed to discern the probable mechanism of drug-resistance for the V82F/I84V mutant of HIV-1 protease (Val82Phe/Ile84Val), and a potential new target site for drugs (i.e., for allosteric inhibitors) was discovered in the process. A new method of drug design was developed that incorporates the flexibilities of both the protein target as well as of the ligand. This Relaxed Complex method was then applied to HIV-1 protease, and a potential new inhibitor has been designed against the V82F/I84V drug-resistant mutant of HIV-1 Protease.