Pharmacophore Modelling of Vanillin Derivatives, Favipiravir, Chloroquine, Hydroxychloroquine, Monolaurin and Tetrodotoxin as MPro inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

Abstract

Ligand-based pharmacophore modelling approach using four established antiviral drugs, namely remdesivir, lopinavir, ritonavir and hydroxychloroquine were analysed for COVID-19 inhibitors as training sets. Twenty vanillin derivatives together with monolaurin were used as test sets to evaluate potential as SARS-CoV-2 inhibitors. Structure-based pharmacophore modelling approach was also performed using Protein Data Bank information: PDB-5RE6, 5REX and 5RFZ in order to analyse the binding site and ligand-protein complex interactions. The pharmacophore modelling mode of 5RE6 displayed two Hydrogen Bond Acceptors (HBA) and one Hydrophobic (HY) interaction. Besides, the pharmacophore model of 5REX showed two HBA and two HY interactions. Finally, the pharmacophore model of 5RFZ showed three HBA and one HY interaction. Based on ligand-based approach, 20 Schiff-based vanillin derivatives, namely vanillin associated with methyl-6- aminopyridine-3-carboxylate (1), sepiapterin (2), 6-aminopyridine-3-carboxylic acid (3), 6-aminopyridine-2-carboxylic acid (4), pemoline (5), α-phenylglycine (6), 2-amino-4-hydroxy-3-methylpentanoic acid (7), 4-hydroxyphenylglycine (8), β-homoserine (9), allylglycine (10), oxamic acid (11) benzophenone hydrazine (12), 2-aminoadipic acid (13), D-alanyl-D-alanine (14), p-bromophenylalanine (15), nicotinic hydrazide (16), 4-hydroxybenzhydrazide (17), benzohydrazide (18), isonicotinic hydrazide (19), and phenylhydrazine (20) showed strong MPro inhibition activity. This was due to their good alignment and common features to PDB-5RE6. Similarly, monolaurin and tetrodotoxin displayed some significant activity against SARS-CoV-2. From structure-based approach, vanillin derivatives (1) to (12) displayed some potent MPro inhibition against SARS-CoV-2. Favipiravir, chloroquine and hydroxychloroquine also showed some significant MPro inhibition. Favipiravir showed good alignment and common pharmacophore features to PDB- 5RFZ, whereas chloroquine and hydroxychloroquine showed good alignment and common pharmacophore features to PDB-5REX.