Antifungal Activity of a Secondary Metabolite of Azadirachta Indica and Its Derivatives – An in Silico Study

Abstract

Objective: This study was aimed to inhibit the 1, 3 β-glucan synthase with azadirachtin or with the derivatives by docking method. Methods:The homology model of the protein 1, 3 β glucan synthase was prepared with "easy modellar" using query sequence and template and it was validated with procheck of Ramachandran plot. The ligand was selected from the PubChem database, and the .sdf file was downloaded which was converted to another file format with open babel. The .pdb files of protein and ligand were uploaded for rough docking with iGEMDOCK, and finally, the accurate docking was made with autodock vina. The docked poses were visualized with PYMOL then saved. The derivatives of the ligand were generated with SWISS ADME, free online software, and selected the derivative for docking. Results:The results obtained from iGEMDOCK and Autodock Vina were tabulated. It was found out that the Azadirachtin and the derivatives are effective in binding 1, 3 β Glucan synthase and thereby inhibiting the formation and integrity of fungal cell wall. Conclusion:In this study, the secondary metabolite Azadirachtin and the derivatives are showing inhibitory action against the model protein 1, 3 β glucan synthase and it was suggested that the external application of the ligand and its derivatives can be used because of their poor oral bioavailability.

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“…The drug likeliness 8,13 and lead likeliness of the compounds retrieved from GC-MS analysis of an aqueous extract of L. alba are follow the Lipinski's rule [14][15][16][17] of 5 except Naphthalene and Phthalic acid, di(2-propylpentyl) ester" with one violation each; the Ghose rule 15,17,18 is not followed by the compounds "Naphthalene'' with two violations, "Benzofuran, 2,3-dihydro-" and "1(3H)-Isobenzofuranone" with three violations, "Thymol", "dl-Erythro-1-phenyl-1,2-propanediol", "Ethanone, 1-(2-hydroxy-5-methylphenyl" and "Phthalic acid, di(2-propylpentyl) ester" with one violation; Veber rule 15,17,19 and Egan rule 15,17,20 is not followed by only "Phthalic acid, di(2propylpentyl) ester"; but only "Ethanone, 1-(2hydroxy-5-methylphenyl" is following the Muegge's rule 17,21 and the bioavailability score 8 for all the compounds is 0.55 and synthetic accessibility score is between 1.00 to 4.35 for all the compounds. The toxicity profile of the compounds that retrieved from GC-MS analysis of aqueous extract of L. alba, by using admetSAR 10,11 web server, the compounds "Ethanone, 1-(2-hydroxy-5-methylphenyl" and "1(3H)-Isobenzofuranone" are AMES mutagenic but not other compounds which is commonly used to screen to determine the mutagenic potential of new chemicals and drugs; all the compounds exhibit acute oral toxicity as category III which means LD 50 value is greater than 500 mg kg -1 but less than 5000 mg kg -1 except & " Phthalic acid, di(2-propylpentyl) ester" which the LD 50 value is greater than 5000 mg kg -1 ; "Phthalic acid, di(2-propylpentyl) ester" shows hERG inhibition leads to Q-T prolongation; "Naphthalene", "Benzofuran, 2,3-dihydro-" and "Phthalic acid, di(2-propylpentyl) ester" shows carcinogenicity as warning sign means the TD 50 is above 10 mg per kg body weight per day and others are non-carcinogenic; all the compounds except "Ethanone, 1-(2-hydroxy-5 -methylphenyl" shows eye irritation; fish aquatic toxicity is exhibiting with "Benzofuran, 2,3-dihydro-" and "dl-Erythro-1- The above Fig.…”