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.