The discovery of potentially selective human neuronal nitric oxide synthase (nNOS) Inhibitors: a combination of pharmacophore modelling, CoMFA, virtual screening and molecular docking studies

Abstract

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.

Figure 1.

Plot of the STERICS, ENERGY and HBOND values for the models with the top ten Specificity values. (a) 3D plot; (b) plot of STERICS vs. ENERGY; (c) plot of ENERGY vs. HBOND; (d) plot of STERICS vs. HBOND. The red cross represents MODEL_12.

Figure 2.

Selected pharmacophore MODEL_012 and the molecular alignment of the compounds used to elaborate the model.

Figure 3.

Correlation between the experimental and CoMFA (Comparative Molecular Field Analysis) predicted activities of compounds.

Figure 4.

(a) CoMFA steric contour maps and (b) CoMFA electrostatic contour maps.

Figure 5.

Virtual screening flowchart.

Figure 6.

(a) Mapping of the hit molecule (AG_205/36953325) by MODEL 012 from SPECS databases; (b) The orientation of AG_205/36953325 in the active site of nNOS; (c) The secondary structure of the active site and AG_205/36953325; and (d) The MOLCAD (a software package of SYBYL) cavity depth potential surfaces structure of the binding site within AG_205/36953325. The cavity depth color ramp ranges from blue (outside of the pocket) to light red (cavities deep inside the pocket).