Abstract Wrk2-04: Virtual screening of ultra-large chemical spaces for novel chemotype discovery

Abstract Recently, 'tangible' virtual libraries have made billions of molecules readily available. Prioritizing these molecules for synthesis and testing demands computational approaches, such as docking. We will present recent results in which protein structure is interrogated using molecular docking, resulting in new high-affinity compounds that exhibit new biology in animal models. Singh I, Seth A, Billesbølle CB, Braz J, Rodriguiz RM, Roy K, Bekele B, Craik V, Huang XP, Boytsov D, Pogorelov VM, Lak P, O'Donnell H, Sandtner W, Irwin JJ, Roth BL, Basbaum AI, Wetsel WC, Manglik A, Shoichet BK, Rudnick G. Structure-based discovery of conformationally selective inhibitors of the serotonin transporter. Cell. 2023 May 11;186(10):2160-2175.e17. doi: 10.1016/j.cell.2023.04.010. Epub 2023 May 2. PMID: 37137306; PMCID: PMC10306110. Fink EA, Xu J, Hübner H, Braz JM, Seemann P, Avet C, Craik V, Weikert D, Schmidt MF, Webb CM, Tolmachova NA, Moroz YS, Huang XP, Kalyanaraman C, Gahbauer S, Chen G, Liu Z, Jacobson MP, Irwin JJ, Bouvier M, Du Y, Shoichet BK, Basbaum AI, Gmeiner P. Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor. Science. 2022 Sep 30;377(6614):eabn7065. doi: 10.1126/science.abn7065. Epub 2022 Sep 30. PMID: 36173843; PMCID: PMC10360211. Kaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, Kweon OS, Che T, McCorvy JD, Kamber DN, Phelan JP, Martins LC, Pogorelov VM, DiBerto JF, Slocum ST, Huang XP, Kumar JM, Robertson MJ, Panova O, Seven AB, Wetsel AQ, Wetsel WC, Irwin JJ, Skiniotis G, Shoichet BK, Roth BL, Ellman JA. Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity. Nature. 2022 Oct;610(7932):582-591. doi: 10.1038/s41586-022-05258-z. Epub 2022 Sep 28. PMID: 36171289; PMCID: PMC9996387. Citation Format: J. Irwin. Virtual screening of ultra-large chemical spaces for novel chemotype discovery [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr Wrk2-04.