Bionics Design of Affinity Peptide Inhibitors for SARS-CoV-2 RBD to Block SARS-CoV-2 RBD-ACE2 Interactions

Novel coronary pneumonia, that is, the coronavirus disease in 2019 (COVID-19), has already posed serious threats and impacts on the health of the population and the country's economy. Therefore, it is of great theoretical significance and practical application value to better understand the process of 2019-nCoV infection and develop effective therapeutic drugs based on this. Previous studies have shown that the receptor-binding structural domain (SARS-CoV-2 RBD) on the spike protein of the novel coronavirus directly mediates its interaction with the host receptor angiotensin-converting enzyme (ACE2), but the mechanism of interaction between SARS-CoV-2 RBD-ACE2 is still unclear. Firstly, the kinetic process of the SARS-CoV-2RBD-ACE2 composite structure was studied by using the full-atom molecular dynamics simulation (MD). Then, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculation method was used to explore the interaction mechanism between SARS-CoV-2RBD-ACE2. The results of energy analysis showed that the key residues Arg403, Arg408, Lys417, and Tyr505 of SARS-CoV-2 RBD and the key residues Asp30, Glu37, Asp38, and Tyr41 of ACE2 were identified. Then, based on the hotspot residues of ACE2 and their distribution, a short peptide library of high-affinity SARS-CoV-2 RBD was constructed. And using molecular docking virtual screening to obtain short peptides with high affinity for SARS-CoV-2 RBD, including DDFEDY, DEFEDY, DEYEDY, DFVEDY, DFHEDY, and DSFEDY. The results of MD simulation confirmed that DDFEDY, DEYEDY, and DFVEDY are expected to be effective inhibitors. Finally, the allergenicity, toxicity and solubility properties of the three peptide inhibitors were validated. Funding Information: This work was funded by the National Key R&D Program (No. 2021YFC2102700), the National Natural Science Foundation of China (Nos. 21908165 and 21878234), the project of Novel Coronavirus Prevention and Treatment of Tianjin University of Science & Technology (No. 2020STCV0018) and Regional Innovation System Project (No. 21ZYQCSY00050) Declaration of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.