title: Insights into ligand selectivity in nitric oxide synthase isoforms: a molecular dynamics study.
abstract: Molecular dynamics (MD) simulations were carried out for inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) isoforms complexed with substrate (L-arginine) and the iNOS specific inhibitor GW 273629, 2 for a time period of 1.2ns. The simulations were compared both within and across the isoforms. iNOS specificity of inhibitor 2 is attributed to water mediated interactions and cooperative hydrogen bond networks. Juxtaposition of the carboxylic and ammonium groups in the substrate and inhibitor serve as a modulating key in binding to the isoforms. Based on these investigations, molecules 3 and 4 were rationally designed to attain specificity among the isoforms. The capability of the designed ligands was theoretically tested through MD simulations to envisage binding patterns with both isoforms. A detailed analysis of the molecular recognition pattern shows molecule 4 to be more selective to iNOS when compared to eNOS.
authors.affiliation: School of Chemistry, University of Hyderabad, Hyderabad 500046, India.
authors.forename: V
authors.initials: V
authors.lastname: Aparna
authors.forename: G R
authors.initials: GR
authors.lastname: Desiraju
authors.forename: B
authors.initials: B
authors.lastname: Gopalakrishnan
mesh_terms: D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000737:chemistry* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: C409003:GW 273629; D008024:Ligands; D020033:Protein Isoforms; D013450:Sulfones; D014867:Water; D001120:Arginine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III