Virtual screening for early identification of potent and selective histone deacetylase 6 inhibitor series

Shawn J Stachel; Deping Wang; Anthony T Ginnetti; Shahriar Niroomand; Lei Ma; YingHui Hu; John F Fay; Wei Lemaire; Daniel J Krosky; Andres D Ramirez; Hatim A Zariwala; Paul J Coleman

doi:10.1016/j.bmcl.2023.129537

Virtual screening for early identification of potent and selective histone deacetylase 6 inhibitor series

Bioorg Med Chem Lett. 2023 Oct 27:129537. doi: 10.1016/j.bmcl.2023.129537. Online ahead of print.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
² Department of Structural Biology, Merck & Co., Inc, PO Box 4, West Point, PA 19486, USA.
³ Department of Neuroscience, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
⁴ Department of Pharmacology Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.

PMID: 39491120
DOI: 10.1016/j.bmcl.2023.129537

Abstract

Virtual screening was leveraged to identify novel series of histone deacetylase 6 (HDAC6) inhibitors prior to conducting a high-throughput screen. The virtual screen was designed to augment and expand on chemical matter that would otherwise be unavailable for high-throughput screening. Through this effort we succeeded in identifying four novel, potent and highly selective HDAC6 inhibitor series. These series displayed favorable ligand binding efficiencies and good potential for further optimization. The virtual design specifications and results are discussed herein.

Keywords: ALS; HDAC6; Histone deacetylase inhibitors; Virtual screening.