Rational design of 3CLpro inhibitors: role of functional group identity and position in ligand-protein interactions

The main protease (3CLpro) is an effective molecular target for the treatment of novel coronavirus. Therefore, the rational design of effective 3CLpro inhibitors is imperative. Given that the ligand–protein interactions are largely dictated by functional groups, the strategic optimisation of these groups emerges as a pivotal approach. In this study, 31 novel compounds were designed by introducing different types and lengths of functional groups at three sites (X, Y, and Z) of Raltegravir. These novel compounds were evaluated for toxicity, and the results confirmed their safety. The docked and MM-PBSA binding free energy results showed that the compounds with functional groups introduced at position Z had the best binding strength to 3CLpro. The interaction mechanism between the compounds and the main protease was analysed by calculating the RMSD, RMSF, H-bonds, DCCM, PCA, and FEL of the complexes. The complexes with the longest functional groups showed large RMSF fluctuations during the MD simulation. All the novel compounds showed high binding affinity to 3CLpro, and Z7, which contains a –COOH functional group, was the best compound. This study aimed to develop novel 3CLpro inhibitor by improving functional groups, and provide a theoretical basis for the design of novel coronavirus drugs.