Knowing how and where to focus chemistry design efforts is key to rapidly progressing the potency of a chemical series. A computational method named WaterMap has been developed to facilitate such efforts by calculating the locations and thermodynamic characteristics of water sites in a binding pocket. I will begin with a short overview of the theory underlying WaterMap and then review some of its early successes in drug discovery programs. Then, I will discuss a recent example in which WaterMap was used not only prospectively to develop inhibitors of the SARS-CoV-2 main protease with non intuitive features but also to rationalize steep activity cliffs in the series under investigation.<br/><br/><i>This talk is dedicated to the memory of Dr. Jeremy Greenwood (1971-2022), an early proponent of WaterMap and the importance of waters in drug discovery.</i>

WaterMap: Theory and application to the development of SARS-CoV-2 main protease inhibitors

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