Accelerated Drug Design Through Computational Biology

Our initiative to design agents to combat Plasmodium falciparum, the most debilitating of several malaria strains, combines powerful bioinformatic techniques to develop protein target structures with a multifaceted strategy for rational drug design. Using the available x-ray crystal structure of CDK2 as a structural template, we will generate and validate three-dimensional structural models of the P. falciparum kinases using computer-based homology modeling techniques. These models, together with structures available for mammalian CDKs, will enable us to employ a battery of computer-assisted rational drug design techniques, including a proprietary tool called Shape Signatures, to accelerate the identification of drug candidates that not only are potent antimalarial agents but also selectively inhibit P. falciparum over human CDKs. The limited success of prior compounds examined under these criteria may be attributed to "off the shelf" testing rather than their rational design. This study will remedy this shortcoming by employing computer-assisted drug design approaches to exploit differences in key ligand-binding residues within Pfmrk versus mammalian CDKs. Our modeling study of PfPK5 is provided as proof-of-concept. This design strategy is further enhanced by our expertise in protein expression, assay development and execution such that lead validation provides rapid iterative feedback to the molecular design process.