Effect of computationally designed fragment-based analogs on the RBD–ACE2 complex of the SARS-CoV-2 P.1 variant†

The binding of the receptor binding domain (RBD) of spike protein to the human ACE2 receptor is the primary step in the SARS-CoV-2 infection process. Spike protein has been an important therapeutic target. Emerging variants of SARS-CoV-2 have been imposing a significant challenge. Variants, especially with mutations on the RBD of spike protein, provide enhanced affinity towards the hACE2 receptor compared to the wild-type. Despite the development of many therapeutics, their efficacy towards the variants remains poor. In the present study, we used a fragment replacement approach to probe the fragment's space for analog design. We screened various fragments based on the geometric requirements to fit within the specified local environments of the RBD–ACE2 complex. Among all the screened analogs, two showed a better binding affinity with the RBD–ACE2 complex of the P.1 variant. Our all-atom simulations and free-energy calculations revealed a stable interaction of analogs with the interface residues of the RBD–ACE2 complex. The binding of analogs influenced the interactions of the key residues and led to structural interference in the complex. Essential dynamics analysis revealed that both analogs induce a change in the dynamic motion throughout the complex. The designed analogs may modulate the dynamics of the RBD–ACE2 complex formation and can be used as one of the lead molecules to interfere with the initial infection process of COVID-19 infections.