Theoretical and Computational Chemistry

Enhanced Sampling of Chemical Space for High Throughput Screening Applications using Machine Learning



In drug discovery applications, high throughput virtual screening exercises are routinely performed to determine an initial set of candidate molecules referred to as "hits". In such an experiment, each molecule from large small-molecule drug library is evaluated for physical property such as the binding affinity (docking score) against a target receptor. In real-life drug discovery experiments, the drug libraries are extremely large but still a minor representation of the essentially infinite chemical space , and evaluation of physical property for each molecule in the library is not computationally feasible.
In the current study, a novel machine learning framework "MEMES" based on Bayesian optimization is proposed for efficient sampling of chemical space. The proposed framework is demonstrated to identify 90% of top-1000 molecules from a molecular library of size about 100 million, while calculating the docking score only for about 6% of the complete library. We believe that such a framework would tremendously help to reduce the computational hour and resources in not only drug-discovery but also areas that require such high-throughput experiments.


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Supplementary material

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docking hits SI