Structure-based drug design has been a centerpiece of drug discovery and has underpinned the understanding of small-molecule-protein interactions. Protein-ligand structures provide excellent starting points to begin new drug discovery projects and the structure and dynamics of a binding site provide direction for identifying new lead series, creating new ligands and typically providing increased efficiency as new structure-activity relationships (SAR) are explored. Many fairly simple principles and calculations will be reviewed that are helpful in organizing the creative chemical space of drug discovery within novel protein targets. A project based on inhibiting the Artemis enzyme will be used to illustrate the value and difficulties encountered in typical structure-guided projects. Artemis is an oncology target that serves as a metal-catalyzed endonuclease. At the beginning of the project, only limited structural information was available for lead-series discovery and the binding site was limited to a bimetallic, catalytic active site. A likely distal binding site was identified by computation and then verified with a collaborative process. High throughput screening of a diverse library of chemical structures provided non-metal binding hits. Co-crystal structures of the hits verified the binding modes in the suspected distal site. The inhibitory activity of each series was improved through collaboration among computational chemistry, medicinal chemistry and structural biology. An analysis of the various computations that were used, the insights gained and retrospective analysis of the accuracy of several computational methods will be presented.

Exploring structure-activity relationships with computations and structure-guided drug discovery: Examples from a DNA repair enzyme

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ACS Spring 2023

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