SYNTHESIS AND IN SILICO STUDIES OF NOVEL ANTI-SARS-COV SULFONAMIDES AS POTENTIAL INHIBITORS AGAINST COVID-19 PROTEIN TARGET: SARS-COV-2 MAIN PROTEASE (M PRO )

摘要

A cluster of pneumonia cases and COVID-19 pandemic that started in Wuhan, China, was caused by novel beta coronavirus, the 2019 novel coronavirus (2019-nCoV). This has led to many number of deaths and many were infected worldwide owing to the absence of effective therapies against coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2). Viral maturation requires the activity of the main viral protease (Mpro) and thereby, inhibition stops the advancement of the disease. The current invention delivers a potential anti-viral drug candidates docked against COVID-19 protein targets: SARS-CoV-2 main protease, drug-likeness, efficacy, molecular docking, physicochemical and pharmacokinetic studies of novel synthesized sulfonamide analogues. Physicochemical and pharmacokinetic properties have been evaluated on the basis of certain parameters like Lipinski rule of 5 (RO5 rule) and ADMET (absorption, distribution, metabolism, excretion and toxicity). All the synthesized compounds follow Lipinski rule of five (RO5 rule) and the compounds followed the range of rotational bonds, hydrogen bond acceptors (HBA), hydrogen bond donors (HBD), topological surface area (TPSA), number of violations, etc. All these compounds shown good pharmacokinetic properties, zero renal OCT2 substrate toxicity and negligible toxicity values. BOILED-egg model was carried out for evaluating the gastrointestinal absorption and brain penetration effect. Compounds 3b and 3d comes under white region of egg and exhibited good gastrointestinal absorption, whereas, 3a, 3c, 3e and 3f compounds fall under yellow region (yolk) of egg which showed good brain penetration effect. All novel sulfonamide analogues including commercially available anti-COVID-19 drugs, Hydroxychloquine and Umifenovir docked with COVID-19 protein targets, i.e., PDB: 6VWW & 6Y2E.Compound 3c when docked with PDB: 6VWW shown maximum energy of -22.06 kcal/mol with two hydrogen binding interactions which are better than marketed drugs. Similarly, compound 3a exhibited highest energy of -14.00 kcal/mol.