l-Arginine Binding to Human Inducible Nitric Oxide Synthase: An Antisymmetric Funnel Route toward Isoform-Specific Inhibitors?

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• 作者：Nicolas Floquet ; Jean-Franc抬ois Hernandez ; Jean-Luc Boucher ; Jean Martinez
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2011
• 出版时间：June 27, 2011
• 年：2011
• 卷：51
• 期：6
• 页码：1325-1335
• 全文大小：1323K
• 年卷期：v.51,no.6(June 27, 2011)
• ISSN：1549-960X

文摘

Nitric oxide (NO) is an important signaling molecule produced by a family of enzymes called nitric oxide synthases (NOS). Because NO is involved in various pathological conditions, the development of potent and isoform-selective NOS inhibitors is an important challenge. In the present study, the dimer of oxygenase domain of human iNOS (iNOSoxy) complexed to its natural substrate l-arginine (l-Arg) and both heme and tetrahydro-l-biopterin (BH4) cofactors was studied through multiple molecular dynamics simulations. Starting from the X-ray structure available for that complex (PDB: 1NSI), a 16 ns equilibration trajectory was first obtained. Twelve dynamics of slow extraction of l-Arg out from the iNOSoxy active site were then performed. The steered molecular dynamics (SMD) approach was used starting from three different points of the reference trajectory for a total simulation time of 35 ns. A probable unbinding/binding pathway of l-Arg was characterized. It was suggested that a driving force directed the substrate toward the heme pocket. Key intermediate steps/residues along the access route to the active site were identified along this 鈥渇unnel shape鈥?pathway and compared to existing data. A quasi-normal mode analysis performed on the SMD data suggested that large collective motions of the protein may be involved in l-Arg binding and that opening the route to the active site in one monomer promoted an inverse, closing motion in the second monomer. Finally, our findings might help to rationalize the design of human iNOS isoform competitive inhibitors.