Discovery of Novel Small-Molecule Inhibitors of SARS-CoV-2 Main Protease as Potential Leads for COVID-19 Treatment

Abstract

The main protease of SARS-CoV-2 virus, Mpro, is an essential element for viral replication, and inhibitors targeting Mpro are currently being investigated in many drug development programs as a possible treatment for COVID-19. An in vitro pilot screen of a highly focused collection of compounds was initiated to identify new lead scaffolds for Mpro. These efforts identified a number of hits. The most effective of these was compound SIMR-2418 having an inhibitory IC50 value of 20.7 μM. Molecular modeling studies were performed to understand the binding characteristics of the identified compounds. The presence of a cyclohexenone warhead group facilitated covalent binding with the Cys145 residue of Mpro. Our results highlight the challenges of targeting Mpro protease and pave the way toward the discovery of potent lead molecules.

Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

“…As highlighted in the previous sections, we reported some examples of ligand/structure-based, hybrid or nonhybrid, virtual screenings, and new computational approaches that led to biologically interesting compounds. In some cases, the integration of noncovalent and covalent docking protocols led to compounds with optimal interaction with both the catalytic cysteine and the other amino acids residues in the clefts of the binding site. , Furthermore, QSAR and/or pharmacophore modeling approaches combined with molecular docking, MD simulations, and free binding energy MM/PBSA enabled the development of new derivatives with promising covalent SARS-CoV-2 M PRO inhibitory activity. ,,,− , …”

“…The presence of a cyclohexenedione fragment is essential for the covalent inhibition, while the tert -butyl group fits deeply into a hydrophobic cleft. 71 …”

“…Molecular docking and dynamics analyses showed that the unexplored core, based on the fusion between a benzo­[ b ]­[1,4]­oxazin-6­(5 H )-one and an imidazo­[2,1- b ]­thiazole system, is crucial to achieve the desired orientation in the active site of the target protein. The presence of a cyclohexenedione fragment is essential for the covalent inhibition, while the tert -butyl group fits deeply into a hydrophobic cleft …”

Computationally driven discovery of SARS-CoV-2 Mproinhibitors: from design to experimental validation

“…Many studies have been devoted to the design of new M pro inhibitors 3,5,[15][16][17][18][19][20][21][22][23][24][25] through joint computational and experimental approaches. In particular, a recent study by the Jorgensen group highlighted the usefulness of relative binding free energy (RBFE) computations as part of the drug design process.…”

In silico exploration of disulfide derivatives of Ferula foetida oleo-gum (Covexir®) as promising therapeutics against SARS-CoV-2

“…Therefore, numerous studies were conducted to find more efficient drugs to combat COVID-19 [ 11 , 12 ]. Accordingly, several computational studies have been reported to examine many potential inhibitors of SARS-CoV-2 main protease [ [13] , [14] , [15] ].…”