Targeting drug resistance: Identifying allosteric binding sites, exploiting conserved allosteric networks with enhanced sampling computational method

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The problem of drug resistance is common to many targets, including anti-microbial and anti-cancer targets (e.g. kinases). It is increasingly clear that allosteric inhibitors, alone or in combination with orthosteric ones can be used to modulate targets harboring drug-resistant inducing mutations. This 4 year PhD research project, is a collaboration between the UCL Chemistry Department and Institute of Structural and Molecular Biology at UCL and AstraZeneca Ltd, a global biopharmaceutical company. The aim of this EPSRC CASE PhD project is to further optimize the simulation methodologies from the Gervasio's group and apply them to understand the allosteric regulation of Drug resistant targets such as Beta-lactamases (antimicrobial resistance) and anticancer-tagets harbouring drug-resistance inducing genetic mutations. The emergence of drug resistance is one of the most serious problems for global health care, requiring innovative solutions in the design of drugs. Here we will use enhanced sampling simulations to understand the molecular mechanisms of allosteric regulation in these targets