This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The purpose of this proposal is to request a 10,000 hour development allocation for the Teragrid system. We will use this allocation to benchmark calculations for future larger proposals to improve docking methods for evaluating the relative energetics of molecular interactions and to identify potential chemotherapeutics for relevant biological pathogens with computational tools. The utility of docking depends mainly on two highly coupled parameters:(1) the accuracy of structures and (2) the accuracy of energies. Scoring functions drive both and provide metrics with which to compare different structures and rank potential ligands for affinity with a biological target. Specifically, we aim to implement and test new scoring functions, which use the MPI protocol with the DOCK program, to rank large databases for favorable interactions with a marcromolecular target. These scoring functions will be assessed with a docking test set, which is currently being developed in our laboratory, consisting of clinically relevant receptor-ligand complexes formatted for the appropriate calculations. We intend to use these improved docking methodologies to perform virtual screening of available structure libraries of compounds for binding to a number of important drug targets. Favorably ranked compounds will be tested by our experimental collaborators. Improved computational procedures have the potential to drastically reduce the time and costs associated with drug discovery and development. Our improved procedures will be adapted to study emerging infectious diseases including HIV, SARS-CoV, and the influenza virus.
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