Docking from 3D structural databases, molecular mechanics, molecular and Brownian dynamics, electrostatics, quantum mechanics, QSAR, and other methods are used in the work mentioned above. The HIV-1 integrase splices the proviral genome into the host DNA thereby tricking the host cell machinery into making viral proteins. Our early results on this project are providing some clues about the structure of the active site. The initial small molecule docking studies have revealed hot spots for new functional group types that we are incorporating into newly designed lead compounds. A dynamic pharmacophore method has been developed that takes protein flexibility into account, which appears very promising.
Studies are also underway on the dynamics and inhibition of bacterial alanine racemases.
These enzymes are found only in bacteria and are required for the first step in enzymatic synthesis of the peptidoglycan layer. These enzymes represent targets for broad spectrum anti-bacterial drug design efforts. We start with three-dimensional structures of alanine racemases, carry out molecular dynamics simulations, docking calculations, and finally database searching in order to under the function and inhibition of these enzymes, and to identify novel potential new drug candidates. We have a collaboration with a biochemistry group in this department to assist in the rational redesign of the substrate binding pocket for the leucyl tRNA synthetase. In this way, non-natural amino acids might then be more easily incorporated into proteins during protein biosynthesis.