Lead optimization: using MD to improve potency and selectivity in PTP-1B inhibitors

COMP 64

Christopher I. Bayly1, Cheuk K. Lau1, J.Y. Gauthier2, Chun Li3, Michel Thérien2, Ernest Asante-Appiah4, W Cromlish2, Yves Boie4, Farnaz Forghani4, S Desmarais5, Qingping Wang4, K Skorey5, D Waddleton5, Paul Payette4, C Ramachandran5, B Kennedy2, and Giovana Scapin6. (1) Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, QC H9H 3L1, Canada, (2) Merck Frosst Centre for Therapeutic Research, (3) Medicinal Chemistry Department, Merck Frosst Canada & Co, 16711 route Transcanadienne, Kirkland, QC H9H 3L1, Canada, (4) Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, QC QC H9H 3L1, Canada, (5) Merck Frosst Canada Inc, QC, Canada, (6) Department of Medicinal Chemistry, Merck Research Laboratory, P.O. Box 2000, Rahway, NJ 07065
Structure-based design encompasses a range of methods from fast and cheap through to slow and expensive. Applying the latter needs to be “worth it” in the context of medicinal chemistry priorities and timeliness. The usefulness of full-scale molecular dynamics using periodic boundary conditions and explicit water will be demonstrated in the context of the lead optimization of small-molecule phosphotyrosine phosphatase 1B (PTP-1B) inhibitors to improve PTP-1B potency and introduce modest selectivity against the highly similar anti-target T-cell phosphotyrosine phosphatase.