A Cloud-Based Web Application to Accelerate Targeted Covalent Drug Discovery

Project Summary Abstract Covalent drug discovery is gaining increasing interest and clinical successespecially for cancer and infectious diseasesAlthough old covalent drugs were discovered serendipitouslymodern covalent drug discovery takes a rational approachWhile chemical intuition and trial and error are helpfulthe discovery process can be signi cantly shortened by the knowledge of whether the intended engagement site is suf ciently nucleophilic and whether alternative reactive sites are availableAnother gap that the proposal seeks toll is the lack of commercial tools for accurate and reliable prediction of protonation states of proteins and other macromoleculesProtonation states of proteins can change upon bindingand incorrect assignment of protonation states can lead to erroneous dockingscoring resultsand inaccurate binding af nity calculationsKnowledge of protonation states is particularly relevant for drug design involving pH sensitive targetssuch as the highly pursued proteases and kinaseswhich often change protonation states upon activation or deactivationThe objective of this project is to develop a cloud based web application to predict reactive hotspots in proteins and more broadly the pKa values of any titratable sites in macromoleculesIn Aimwe plan to further improve and validate continuous constant pH molecular dynamics for predicting pKaandapos s and reactive hotspots in proteinsIn Aimwe plan to develop a on demand web application based on the continuous constant pH molecular dynamics tool and cloud computing paradigm for assisting drug and materials designThis unique product can be used to assist the discovery of novel covalent inhibitorsidenti cation of new drug targetsand mechanistic studies of covalent inhibitionAdditionallyit can be incorporated in the current work ow of structure based drug design to improve the outcomes of dockingscoringbinding af nity calculationsand molecular dynamics simulations Project Narrative Covalent inhibition is becoming a widely pursued alternative therapeutic strategy for cancerinfectiousand immunological diseasesThis project seeks to develop a cloud based on demand web application that offers rapid and accurate predictions of covalently targetable hotspots in proteins and more broadly the protonation states of any titratable sites in macromolecules to accelerate drug discovery