A high-throughput FEP pipeline for optimisation of hits into leads for novel drug targets

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Free Energy Perturbation (FEP) methods are increasingly used in industry to guide potency optimisation of preclinical candidate compounds. FEP methods are well suited to optimise compounds for novel drug targets amenable to structure-based drug design as they can deliver high accuracy potency predictions without requiring a prior training set of active compounds. However the performance of FEP varies across target classes (e.g. kinases, GPCRs) and can be affected by the choice of the FEP implementation. Currently significant technical expertise is required to deploy FEP effectively in an industrial R&D setting.The goal of this research is to develop an optimised open source FEP implementation for robust performance across broad range of drug target classes. Systematic comparison of leading FEP implementations (available via e.g. Amber, Gromacs, OpenMM) will be facilitated by development of easy to use automated pipelines for high throughput FEP studies using the BioSimSpace framework for biomolecular simulation (www.biosimspace.org). Protein-ligand binding free energies will be computed using high performance computing and cloud computing resources for a diverse dataset of drug targets of current interest to Evotec. Lessons learned from these large scale validation studies will drive the implementation of novel algorithms in our in-house FEP software SOMD (www.siremol.org) to improve the accuracy, speed and reliability of FEP. Through periods of placement at Evotec the student will deploy the new software onto internal computing resources and help molecular modellers apply the methodology to real world drug discovery projects.