FLEXIBLE DOCKING USING MODAL METHODS

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The long term objective of this project is to develop a new ligand-receptor docking simulation software code, known as FLEX-DOCK, that features significant improvements in physical realism over current rigid-body docking codes (e.g., DOCK). It is intended to be used as a higher level filter to fill the gap between high speed low fidelity massive data base screening tools and much higher fidelity molecular dynamics modeling or direct laboratory screening via combinatorial chemistry techniques. FLEX-DOCK models the ligand and receptor active site as bodies (groups of atoms) with structural flexibility (degrees-of-freedom) described by component modes. The component mode framework facilitates structural flexibility for both ligand and receptor during the docking simulation. When completed, FLEX-DOCK will enable physically realistic and efficient screening in drug discovery that will result in much higher probability-for-success lead compounds entering the wet chemistry phase than possible from current docking simulation methods. The objectives for Phase II include: (1) completing the development of FLEX-DOCK's modal flexibility for ligand and receptor; and (2) developing a method for generating and storing FLEX-DOCK fbody prescriptions and component modes in the small molecule/ligand data bases that are used for screening in the pharmaceutical industry. PROPOSED COMMERCIAL APPLICATIONS: The improved realism of FLEX-DOCK over current rigid-body docking codes offers to significantly improve the efficiency of lead compound searches for drug design in the pharmaceutical industry. Two commercial applications are planned to take advantage of this opportunity: (1) commercial FLEX-DOCK software, which will be licensed and sold through a computational chemistry software firm; and (2) research services using FLEX-DOCK in support of drug design research for pharmaceutical firm customers.