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Molecules 2017, 22(10), 1588; doi:10.3390/molecules22101588

Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches

1
Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Lira 85, Santiago 8330074, Chile
2
Facultad de Ciencia, Universidad San Sebastián, Campus Los Leones, Lota 2465, Providencia, Santiago 7510157, Chile
3
Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Av. Vicuña Mackenna 4860, Macul, Santiago 7820436, Chile
4
Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Av. Vicuña Mackenna 4860, Macul, Santiago 7820436, Chile
5
Centro de Investigación en Nanotecnología y Materiales Avanzados, CIEN-UC, Pontificia Universidad Católica de Chile, Av. Vicuña Mackenna 4860, Macul, Santiago 7820436, Chile
*
Author to whom correspondence should be addressed.
Received: 28 August 2017 / Revised: 15 September 2017 / Accepted: 18 September 2017 / Published: 22 September 2017
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [7314 KB, uploaded 25 September 2017]   |  

Abstract

Factor Xa (FXa), a vitamin K-dependent serine protease plays a pivotal role in the coagulation cascade, one of the most interesting targets for the development of new anticoagulants. In the present work, we performed a virtual screening campaign based on ligand-based shape and electrostatic similarity search and protein-ligand docking to discover novel FXa-targeted scaffolds for further development of inhibitors. From an initial set of 260,000 compounds from the NCI Open database, 30 potential FXa inhibitors were identified and selected for in vitro biological evaluation. Compound 5 (NSC635393, 4-(3-methyl-4H-1,4-benzothiazin-2-yl)-2,4-dioxo-N-phenylbutanamide) displayed an IC50 value of 2.02 nM against human FXa. The identified compound may serve as starting point for the development of novel FXa inhibitors. View Full-Text
Keywords: factor Xa; virtual screening; shape-based screening; protein-ligand docking; enzyme inhibitors; blood coagulation cascade factor Xa; virtual screening; shape-based screening; protein-ligand docking; enzyme inhibitors; blood coagulation cascade
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lagos, C.F.; Segovia, G.F.; Nuñez-Navarro, N.; Faúndez, M.A.; Zacconi, F.C. Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches. Molecules 2017, 22, 1588.

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