Quantum Chemical Interaction Analysis between SARS-CoV-2 Main Protease and Ensitrelvir Compared with Its Initial...

Area of Science:

• Biochemistry
• Computational Chemistry
• Drug Discovery

Background:

• Ensitrelvir (Xocova) is a non-covalent oral drug developed for SARS-CoV-2 main protease (Mpro) inhibition.
• Structure-based drug design (SBDD) was employed in its development.
• Understanding the molecular basis for improved activity from initial screening compounds to ensitrelvir is crucial.

Purpose of the Study:

• To elucidate the factors contributing to the enhanced inhibitory activity of ensitrelvir against SARS-CoV-2 Mpro.
• To analyze the microscopic interactions between ensitrelvir and Mpro residues using computational methods.

Main Methods:

• Fragment molecular orbital (FMO) calculations were used to analyze interaction energies.
• Inhibitor interactions with each residue of Mpro were quantitatively assessed.
• Conformational changes induced by ensitrelvir binding were investigated.

Main Results:

• Functional group modifications in ensitrelvir significantly strengthened existing interactions with Mpro.
• Novel interactions, including hydrogen bonds, halogen bonds, and pi-orbital interactions, were identified for ensitrelvir.
• Ensitrelvir binding induced conformational changes in Mpro, leading to additional favorable interactions.

Conclusions:

• FMO-based analysis successfully illuminated the microscopic interactions responsible for ensitrelvir's high activity against Mpro.
• The findings highlight the effectiveness of SBDD strategies in optimizing drug candidates.
• Detailed mechanistic insights, including water-mediated interactions, can guide the design of future Mpro inhibitors.