A Quantum Mechanics-Based Method to Predict Intramolecular Hydrogen Bond Formation Reflecting P-glycoprotein Recognition.

Autor:	Oguma T; Laboratory for Medicinal Chemistry Research and Laboratory for Drug Discovery and Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Uehara S; Laboratory for Medicinal Chemistry Research and Laboratory for Drug Discovery and Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Nakahara K; Laboratory for Medicinal Chemistry Research and Laboratory for Drug Discovery and Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Okuyama Y; Laboratory for Medicinal Chemistry Research and Laboratory for Drug Discovery and Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Fuchino K; Laboratory for Medicinal Chemistry Research and Laboratory for Drug Discovery and Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Suzuki N; Laboratory for Medicinal Chemistry Research and Laboratory for Drug Discovery and Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Kan Y; Laboratory for Medicinal Chemistry Research and Laboratory for Drug Discovery and Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Kanegawa N; Laboratory for Medicinal Chemistry Research and Laboratory for Drug Discovery and Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Ogata Y; Laboratory for Medicinal Chemistry Research and Laboratory for Drug Discovery and Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan., Kusakabe KI; Laboratory for Medicinal Chemistry Research and Laboratory for Drug Discovery and Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2023 Jan 13; Vol. 14 (2), pp. 223-228. Date of Electronic Publication: 2023 Jan 13 (Print Publication: 2023).
DOI:	10.1021/acsmedchemlett.2c00427
Abstrakt:	Passive membrane permeability and an active transport process are key determinants for penetrating the blood-brain barrier. P-glycoprotein (P-gp), a well-known transporter, serves as the primary gatekeeper, having broad substrate specificity. A strategy to increase passive permeability and impair P-gp recognition is intramolecular hydrogen bonding (IMHB). 3 is a potent brain penetrant BACE1 inhibitor with high permeability and low P-gp recognition, although slight modifications to its tail amide group significantly affect P-gp efflux. We hypothesized that the difference in the propensity to form IMHB could impact P-gp recognition. Single-bond rotation at the tail group enables both IMHB forming and unforming conformations. We developed a quantum-mechanics-based method to predict IMHB formation ratios (IMHBRs). In a given data set, IMHBRs accounted for the corresponding temperature coefficients measured in NMR experiments, correlating with P-gp efflux ratios. Furthermore, the method was applied in hNK2 receptor antagonists, demonstrating that the IMHBR could be applied to other drug targets involving IMHB. Competing Interests: The authors declare no competing financial interest. (© 2023 American Chemical Society.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu