title: Design and prediction of new anticoagulants as a selective Factor IXa inhibitor via three-dimensional quantitative structure-property relationships of amidinobenzothiophene derivatives.
abstract: Factor IXa (FIXa), a blood coagulation factor, is specifically inhibited at the initiation stage of the coagulation cascade, promising an excellent approach for developing selective and safe anticoagulants. Eighty-four amidinobenzothiophene antithrombotic derivatives targeting FIXa were selected to establish three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models using comparative molecular field analysis and comparative similarity indices analysis methods. Internal and external cross-validation techniques were investigated as well as region focusing and bootstrapping. The satisfactory q (2) values of 0.753 and 0.770, and r (2) values of 0.940 and 0.965 for 3D-QSAR and 3D-QSSR, respectively, indicated that the models are available to predict both the inhibitory activity and selectivity on FIXa against Factor Xa, the activated status of Factor X. This work revealed that the steric, hydrophobic, and H-bond factors should appropriately be taken into account in future rational design, especially the modifications at the 2'-position of the benzene and the 6-position of the benzothiophene in the R group, providing helpful clues to design more active and selective FIXa inhibitors for the treatment of thrombosis. On the basis of the three-dimensional quantitative structure-property relationships, 16 new potent molecules have been designed and are predicted to be more active and selective than Compound 33, which has the best activity as reported in the literature.
authors.affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Jia-Suo
authors.initials: JS
authors.lastname: Gao
authors.affiliation: College of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Xu-Peng
authors.initials: XP
authors.lastname: Tong
authors.affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Yi-Qun
authors.initials: YQ
authors.lastname: Chang
authors.affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Yu-Xuan
authors.initials: YX
authors.lastname: He
authors.affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Yu-Dan
authors.initials: YD
authors.lastname: Mei
authors.affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Pei-Hong
authors.initials: PH
authors.lastname: Tan
authors.affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Jia-Liang
authors.initials: JL
authors.lastname: Guo
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan, USA.
authors.forename: Guo-Chao
authors.initials: GC
authors.lastname: Liao
authors.affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Gao-Keng
authors.initials: GK
authors.lastname: Xiao
authors.affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
authors.affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.
authors.forename: Ping-Hua
authors.initials: PH
authors.lastname: Sun
mesh_terms: D000578:Amidines / Q000737:chemistry / Q000494:pharmacology*; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D015951:Factor Xa / Q000378:metabolism*; D065427:Factor Xa Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000578:Amidines; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D013876:Thiophenes; D015951:Factor Xa
keywords: 3D-QSAR; 3D-QSSR; CoMFA; CoMSIA; benzothiophene antithrombosis
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