Abstract

Objective: To discover inducible Nitric Oxide Synthase (iNOS) inhibitors from Morus sp. and Arcangelisia flava for anti-inflammatory drug candidates.

Methods: The protein crystal structures of human iNOS in complex with AT2 (PDB code: 3E7G) and S-ethylisothiourea (SEITU) (PDB code: 4NOS) were selected, their ligand-protein interaction was studied by employing LigandScout to obtain the pharmacophore features, which were validated against iNOS data base and the result was used to screen the pharmacophores of twenty-nine phytoconstituents in Morus sp. and A. flava. Molecular docking of the phytoconstituents into iNOS binding pocket was performed using AutoDock 4.2.6.

Results: The pharmacophore features obtained were one aromatic ring, one hydrogen bond donor, and one hydrogen bond acceptor, which were proved valid against iNOS training set (GH score = 0.80; AUC100% ROC curve = 0.64 for AT2 and GH score = 0.73; AUC100% ROC curve = 0.65). Ten phytoconstituents in A. flava and eight compounds in Morus sp interact with Glu377, an important amino acid residue in iNOS binding pocket. Sanggenon F of Morus sp indicate the best affinity (docking score -9.88 kcal/mol, respectively), compared to that of SEITU (docking score -5.48 kcal/mol).

Conclusions: Phytoconstituents in Morus sp. and A. flava fit the pharmacophore features generated from AT2 or SEITU complex with iNOS, therefore they might be potential as iNOS inhibitors. Of twenty-nine phytoconstituents, sanggenon F in Morus sp, indicates the best the docking score. Its score is better than SEITU, a known iNOS inhibitor.

Key words: Arcangelisia flava; human iNOS; inflammation; Morus sp.; nitric oxide synthase; yellow root