Dr. James Briggs

Computer-Aided Molecular Design; Molecular Simulations; Protein Structure and Function; Inhibitor Design

Our research is focused on computational studies of protein structure and function, inhibitor design, investigations of possible inhibitor resistance pathways, and development of methods for the above project areas. Targets for these studies include those important in the treatment of AIDS, cancer, bacterial infections, and other disease states. In addition, we work on inhibitors to aid in biowarfare defense (botulinum neurotoxins, anthrax toxin, cholera toxin).

Activities currently underway in my group involve the use and development of computer programs on high-performance computers to study the kinetic and thermodynamic properties of enzymes and receptors. Application areas include the search for inhibitors of the HIV-1 integrase, structural and mechanistic studies of various bacterial enzymes, and more. 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.

Our research is focused on computational studies of protein structure and function, inhibitor design, investigations of possible inhibitor resistance pathways, and development of methods for the above project areas. Targets for these studies include those important in the treatment of AIDS, cancer, bacterial infections, and other disease states. In addition, we work on inhibitors to aid in biowarfare defense (botulinum neurotoxins, anthrax toxin).

Activities currently underway in my group involve the use and development of computer programs on high-performance computers to study the kinetic and thermodynamic properties of enzymes and receptors. Application areas include the search for inhibitors of the HIV-1 integrase, structural and mechanistic studies of various bacterial enzymes, and more. 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.

Antiviral drug design

The HIV-1 integrase splices the proviral genome into the host DNA thereby tricking the host cell machinery into making viral proteins. This enzyme, for which no good inhibitors are known, represents the third of the main enzyme targets in HIV. Work on this project is performed in collaboration among five research groups (X-ray crystallography, virology, computational biochemistry, organic synthesis, and marine biology) that represent a complete structure-based inhibitor design cycle/team. 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.

Antibacterial drug design; Biophysical studies

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. This project represents a collaboration between our group (computational biochemistry) and X-ray crystallography, molecular biology, and organic chemistry research groups. 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.

In addition to the drug design projects, we have interests in the re-engineering of enzyme substrate specificity, and in a number of basic science areas centering on electrostatic properties of biomolecules. 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. We are also interested in developing a method, based on electrostatic properties, for rapidly and reliably predicting locations of specific metal ion binding sites in RNA molecules. The knowledge of such sites is essential to understanding the structures and catalytic mechanisms of RNA molecules. Another example where electrostatic is important in understanding structure and function is for the phosphate binding protein. This protein has a negative electrostatic substrate binding pocket, although the substrate is dianionic (HPO42-) at pH 7. The substrate should be repelled by its binding pocket, so what is the mechanism of attraction of the substrate by the protein? We have revealed the answer to this question by carrying out Brownian dynamics simulations.

Most of the activities in my group are focused on enzymes that are targets for inhibitor design. Greater understanding of the reaction mechanisms, structural dynamics, and of the effects of point mutations should lead to more rational design of next generation inhibitors for these enzymes, that may be less prone to acquired resistance. My group members carry out their calculations on supercomputers, UNIX workstations, and on our Beowulf cluster. I teach courses, at the undergraduate and graduate levels, on the application of molecular modeling techniques to problems of biochemical interest.