Molecular docking studies of a group of hydroxamate inhibitors with   gelatinase-A by molecular dynamics

doi:10.1023/A:1016345810973

CORC > 北京大学 > 化学与分子工程学院

	Molecular docking studies of a group of hydroxamate inhibitors with gelatinase-A by molecular dynamics
	Hou, TJ ; Zhang, W ; Xu, XJ
刊名	计算机辅助分子设计杂志
	2002
关键词	gelatinase-A MMP-2 hydroxamate molecular dynamics molecular docking HUMAN MATRIX METALLOPROTEINASE HUMAN FIBROBLAST COLLAGENASE AUTOMATED DOCKING FORCE-FIELD DESIGN IDENTIFICATION SERRALYSINS SIMULATIONS METZINCINS METASTASIS
DOI	10.1023/A:1016345810973
英文摘要	We have performed docking and molecular dynamics simulations of hydroxamates complexed with human gelatinase-A (MMP-2) to gain insight into the structural and energetic preferences of these inhibitors. The study was conducted on a selected set of eleven compounds with variation in structure and activity. Molecular dynamics simulations were performed at 300 K for 100 ps with equilibration for 50 ps. The structural analyses of the trajectories indicate that the coordinate bond interactions, the hydrogen bond interactions, the van der Waals interactions as well as the hydrophobic interactions between ligand and receptor are responsible simultaneously for the preference of inhibition and potency. The ligand hydroxamate group is coordinated to the catalytic zinc ion and form stable hydrogen bonds with the carbonyl oxygen of Gly 162. The P1' group makes extensive van der Waals and hydrophobic contacts with the nonpolar side chains of several residues in the S1' subsite, including Leu 197, Val 198, Leu 218 and Tyr 223. Moreover, four to eight hydrogen bonds between hydroxamates and MMP-2 are formed to stabilize the inhibitors in the active site. Compared with the P2' and P3' groups, the P1' groups of inhibitors are oriented regularly, which is produced by the restrain of the S1' subsite. From the relationship between the length of the nonpolar P1' group and the biological activity, we confirm that MMP-2 has a pocket-like S1' subsite, not a channel-like S1' subsite proposed by Kiyama (Kiyama, R. et al., J. Med. Chem. 42 (1999), 1723). The energetic analyses show that the experimental binding free energies can be well correlated with the interactions between the inhibitors and their environments, which could be used as a simple score function to evaluate the binding affinities for other similar hydroxamates. The validity of the force field parameters and the MD simulations can be fully testified by the satisfactory agreements between the experimental structure-activity relationship and the information from the structural and energetic analyses. The information generated from the predicted complexes should be useful for further work in the area of structure-based design of new compounds.; http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000176814000003&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701 ; Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications; SCI(E); PubMed; 10; ARTICLE; 1; 27-41; 16
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/200432]
专题	化学与分子工程学院
推荐引用方式 GB/T 7714	Hou, TJ,Zhang, W,Xu, XJ. Molecular docking studies of a group of hydroxamate inhibitors with gelatinase-A by molecular dynamics[J]. 计算机辅助分子设计杂志,2002.
APA	Hou, TJ,Zhang, W,&Xu, XJ.(2002).Molecular docking studies of a group of hydroxamate inhibitors with gelatinase-A by molecular dynamics.计算机辅助分子设计杂志.
MLA	Hou, TJ,et al."Molecular docking studies of a group of hydroxamate inhibitors with gelatinase-A by molecular dynamics".计算机辅助分子设计杂志 (2002).