Dresden 2020 – scientific programme

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CPP: Fachverband Chemische Physik und Polymerphysik

CPP 91: Computational Biophysics (joint session BP/CPP)

CPP 91.9: Talk

Thursday, March 19, 2020, 12:15–12:30, SCH A251

Rational optimization of drug-membrane selectivity by computational screening — •Bernadette Mohr and Tristan Bereau — Max Planck Institute for Polymer Research, Mainz, Germany

Success rates of drug discovery are non-satisfactory considering the high cost in time and resources. This leads to an increased demand for development of improved screening methods. In our work, we explore the capabilities of using a coarse-grained (CG) model to efficiently find candidate structures with desired properties. The Martini CG force field is a physics-based model that incorporates both the essential chemical features with a robust treatment of statistical mechanics. Martini simplifies the molecular representation through a small set of bead types that encode a variety of functional groups present in organic chemistry. This offers two advantages: (i) many molecules map to the same CG representation and (ii) screening boils down to systematically varying among the set of CG bead types available. The combination of these two aspects makes Martini a remarkably efficient candidate for high-throughput screening. We apply this approach to the selective binding of drugs between Cardiolipin and phosphoglycerols in mitochondrial membranes. A systematic screening starting from an already-reported compound will be presented. We identify clear design rules for improved selectivity, and rationalize them on a physical basis. As an outlook, we explore prospects of further boosting screening at higher throughput by means of connecting the CG simulations within a deep-learning framework.