Elucidating the inhibiting mode of AHPBA derivatives against HIV-1 protease and building predictive 3D-QSAR models

doi:10.1021/jm0102710

	Elucidating the inhibiting mode of AHPBA derivatives against HIV-1 protease and building predictive 3D-QSAR models
	Huang, XQ ; Xu, LS ; Luo, XM; Fan, KN ; Ji, RY ; Pei, G ; Chen, KX; Jiang, HL
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2002-01-17
卷号	45 期号:2 页码:333-343
ISSN号	0022-2623
DOI	10.1021/jm0102710
文献子类	Article
英文摘要	The Lamarckian genetic algorithm of AutoDock 3.0 has been used to dock 27 3(S)-amino-2(S)-hydroxyl-4-phenylbutanoic acids (AHPBAs) into the active site of HIV-1 protease (HIVPR). The binding mode was demonstrated in the aspects of the inhibitor's conformation, subsite interaction, and hydrogen bonding. The data of geometrical parameters (tau(1), tau(2), and tau(3) listed in Table 2) and root mean square deviation values as compared with the known inhibitor, kni272,(28) show that both kinds of inhibitors interact with HIVPR in a very similar way. The r(2) value of 0.860 indicates that the calculated binding free energies correlate well with the inhibitory activities. The structural and energetic differences in inhibitory potencies of AHPBAs were reasonably explored. Using the binding conformations of AHPBAs, consistent and highly predictive 3D-QSAR models were developed by performing CoMFA, CoMSIA, and HQSAR analyses. The reasonable r(corss)(2) values were 0.613, 0.530, and 0.717 for CoMFA, CoMSIA,and HQSAR models, respectively. The predictive ability of these models was validated by kni272 and a set of nine compounds that were not included in the training set. Mapping these models back to the topology of the active site of HIVPR leads to a better understanding of vital AHPBA-HIVPR interactions. Structural-based investigations and the final 3D-QSAR results provide clear guidelines and accurate activity predictions for novel HIVPR inhibitors.
WOS关键词	HUMAN IMMUNODEFICIENCY VIRUS ; FREE-ENERGY CALCULATIONS ; ANTIVIRAL ACTIVITY ; AUTOMATED DOCKING ; CRYSTAL-STRUCTURE ; PR INHIBITORS ; BINDING ; RESISTANCE ; PROTEINS ; POTENT
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000173408400011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/274401]
专题	中国科学院上海药物研究所
通讯作者	Jiang, HL
作者单位	1.Fudan Univ, Dept Chem, Shanghai 2000437, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Ctr Drug Design & Discovery,State Key Lab Drug Re, Shanghai 200031, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200032, Peoples R China
推荐引用方式 GB/T 7714	Huang, XQ,Xu, LS,Luo, XM,et al. Elucidating the inhibiting mode of AHPBA derivatives against HIV-1 protease and building predictive 3D-QSAR models[J]. JOURNAL OF MEDICINAL CHEMISTRY,2002,45(2):333-343.
APA	Huang, XQ.,Xu, LS.,Luo, XM.,Fan, KN.,Ji, RY.,...&Jiang, HL.(2002).Elucidating the inhibiting mode of AHPBA derivatives against HIV-1 protease and building predictive 3D-QSAR models.JOURNAL OF MEDICINAL CHEMISTRY,45(2),333-343.
MLA	Huang, XQ,et al."Elucidating the inhibiting mode of AHPBA derivatives against HIV-1 protease and building predictive 3D-QSAR models".JOURNAL OF MEDICINAL CHEMISTRY 45.2(2002):333-343.