The discovery of potentially selective human neuronal nitric oxide synthase (nNOS) Inhibitors: a combination of pharmacophore modelling, CoMFA, virtual screening and molecular docking studies.
Neuronal nitric oxide synthase (nNOS) plays an important role in neurotransmission and smooth muscle relaxation. Selective inhibition of nNOS over its other isozymes is highly desirable for the treatment of neurodegenerative diseases to avoid undesirable effects. In this study, we present a workflow for the identification and prioritization of compounds as potentially selective human nNOS inhibitors. Three-dimensional pharmacophore models were constructed based on a set of known nNOS inhibitors. The pharmacophore models were evaluated by Pareto surface and CoMFA (Comparative Molecular Field Analysis) analyses. The best pharmacophore model, which included 7 pharmacophore features, was used as a search query in the SPECS database (SPECS®, Delft, The Netherlands). The hit compounds were further filtered by scoring and docking. Ten hits were identified as potential selective nNOS inhibitors.
School of Pharmacy, Nanjing Medical University, Nanjing 210029, China. xgh@njmu.edu.cn.
Guanhong
G
Xu
School of Pharmacy, Nanjing Medical University, Nanjing 210029, China. yuechen0311@126.com.
Yue
Y
Chen
School of Pharmacy, Nanjing Medical University, Nanjing 210029, China. mokingsk@sina.com.
Kun
K
Shen
School of Pharmacy, Nanjing Medical University, Nanjing 210029, China. showshow828@163.com.
Xiuzhen
X
Wang
School of Pharmacy, Nanjing Medical University, Nanjing 210029, China. kldlf@njmu.edu.cn.
Fei
F
Li
Department of Internal Neurology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China. kldhy2002@163.com.
Yan
Y
He
D001665:Binding Sites; D062126:Databases, Chemical; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D016018:Least-Squares Analysis; D062105:Molecular Docking Simulation; D009474:Neurons / Q000201:enzymology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship
D004791:Enzyme Inhibitors; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I