Pre-computed free energy maps for rapid structure-based ligand design

RGMPre computed free energy maps for rapid structure based ligand designProject Summary Successful commercial application of computational methods for ligand design requires a platform that provides both qualitative data to direct the design process and rapid production of quantitative data to allow for evaluation of specific ligand possibilitiesIn the proposed study a novel approachSiteIdentification by Ligand Competitive SaturationSILCSwill be further developed to improve its utility as such a platform in the context of the emerging computational chemistry company SilcsBio LLCSILCS involves a one time up front pre conditioning step where the proteinRNA or any macromolecular target is subjected to molecular dynamicsMDsimulations in an aqueous solution of small organic solutes thatfollowing normalization and Boltzmann transformationyieldsD Grid Free EnergyGFEprobability distributionsor GFE FragMapsthat encompass the entire target and may be used for both qualitative and quantitative ligand design approachesBuilding upon our successes in the Phase I SBIRthis Phase II proposal will focus on development of tools to facilitate the application of SILCS to ligand designfurther improving the accuracy of the methodologyand the extension of the technology to the prediction of macromolecular interactionsincluding protein protein interactionsAimis the development of tools to perform a wide range of chemical transformations allowing for rapidseamless quantitative evaluation of theD interaction ofs of ligands with a target on a daily basisThe tools will be integrated with the existing CHARMM General Force Field program to also provide fragment based design capabilities for the development of novel chemical IPAimis improvement in accuracy byadding long range electrostatics to our oscillatingex Grand Canonical Monte CarloGCMCtechnology that already successfully samples deep or occluded pockets such as in GPCRs and nuclear receptorsenhancing conformational sampling of the target protein by Hamiltonian Replica Exchange MD methodsHREMDincluding electronic polarizability by using the classical Drude polarizable force field for calculation of SILCS GFE FragMapsand improved conformational sampling of ligands in the field of the GFE FragMapsAimwill take advantage of the information encoded in the GFE FragMaps to develop a macromolecular docking utility that will account for monomer conformational heterogeneity during docking of one macromolecule with anotherfor the prediction of theD structure of complexes consisting offor exampletwo or more proteinsMeeting the milestones associated with these scientific Aims will directly further our commercialization strategy for SilcsBio LLC by enhancing the value associated with all three of the major business Aimsdirect delivery of SILCS GFE FragMaps and or the SILCS software directly to ligand designe gpharmaceuticalcompanies for in house usepartnering with computational chemistry software vendors to make the SILCS technology accessible to a wider range of ligand design companies andSilcsBio LLC acting as a contract research organizationCROperforming structure based ligand design Public Health Relevance New approaches are required to aid the translation of basic science discoveries into therapeutic agentsProposed is the commercialization of a novel computational technologySite Identification by Ligand Competitive Saturationin the context of an emerging computational chemistry companySilcsBio LLCwhich will allow for the rapid identification and optimization of drug candidatesthereby facilitating their movement into clinical trials with decreased time and financial requirements