An Open Web Service For Fragment-based Design of Small Molecule Inhibitors

SignificanceConifer Point is compiling a vast array of data describing the binding of small chemical fragments to proteinsWe use an innovative Monte Carlo simulator to produce this rigorous dataand use a powerful proprietary search algorithm to mine itThis information uncovers idiosyncratic details about protein binding sites that empower medicinal chemists to design therapeutic compounds which bind in a highly specific fashion to achieve cross protein selectivitymutation avoidanceand high ligand efficiencyaffinity molecular weightOur goal is to provide chemists with affordableready access to powerfulpredictive tools specifically designed to help them generate and prioritize ideas for progressing their hit compoundsdesigns resulting in molecules that optimally bind into the protein targetFragment binding data also enables projects to get started on difficult targets where screening has limited successThis can greatly expand the number of addressable disease targetssuch as protein protein interactionsOur team has uniquely demonstrated the ability to produce fragment maps on a large scalegenerating andgtsuch maps in the last several yearsMore fragment maps enable broader searches to find more chemical possibilitiesOur long term goal is to makes of fragment maps on a fewtherapeutically important proteinsSuch a huge compilation of fragment binding data will be unprecedentedInnovationOver the last decadethe PI and participants on this grant have been employing these fragment water binding maps on dozens of successful pre clinical lead identification projectsbut they were restricted to proprietary commercial effortsOur goal now is to make the information derived from fragment maps available at low cost to a broad community of researchers in drug discoveryWe do this through a novel Web application that provides fragment based design services leveraging the latest Web technologies for browser based computation and integrates with other chemist requested capabilitiesIncluded are water maps ranked by binding free energy that are inexpensive to produceandlt $proteinyet uniquely describe multi body water configurationsComputational chemistry software is poised for a fundamental transition from desktop software to Webbased applications with low cost subscriptions and a broader audienceOur Web application represents the vanguard of this transitionSpecific AimsWe have received feedback from evaluations of our prototype fragment based chemistry design service regarding issues which have led to three specific aimsAimExpand the collection of maps to include proteins fromof the Therapeutic Target Databaseincluding a core set of fragments covering commerciallyavailable fragment compound librariesAimBuild interfaces in the Web application that enable users to define new fragmentsand run incremental fragment map simulations on existing protein structuresAimDramatically improve the performance of the computations for energy minimization to achieve immediate feedback during designOverall ImpactResearchers need alternative approaches to drug lead developmentMining fragment maps is a fertile source of new chemistry ideasWhen widely adoptedthe comprehensive Web service would provide the platform to significantly advance drug discovery Our mission is to provide easy access via the Web to a vast array of data describing the binding ofsmall chemical fragments to proteinsleveraging this data to empower medicinal chemists in addressing the corechallenges of drug discoverySpecificitypotencyand mutation avoidance of drugs require thatcompounds bind to the target protein in a way that exploits the highly idiosyncratic details of theD structure of that protein which are uncovered by the binding of the chemical fragmentsThisprovides chemists with a powerful new tool for generating ideas to resolve conflicting drugoptimization goalsand can greatly expand the number of addressable disease targetssuch asprotein protein interactionsas has been demonstrated