Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

Natalia Fintelman-Rodrigues; Carolina Q. Sacramento; Carlyle Ribeiro Lima; Franklin Souza da Silva; André C. Ferreira; Mayara Mattos; Caroline S. de Freitas; Vinicius Cardoso Soares; Suelen da Silva Gomes Dias; Jairo R. Temerozo; Milene Miranda; Aline R. Matos; Fernando A. Bozza; Nicolas Carels; Carlos Roberto Alves; Marilda M. Siqueira; Patrícia T. Bozza; Thiago Moreno L. Souza

A molecular dynamic analysis revealed that the root-mean-square deviation (RMSD) for the SARS-CoV-2 Mpro backbone presented different conformations in complex with ATV or LPV ( Figure S1 ). LPV was initially at a 3.8 Ã… distance from the catalytic residue Cys145 ( Figure S2A and S3A), which after conformational changes extended to a distance equivalent to 7.17 Ã… ( Figure 3A and 4A) that is projected to most likely limit the extent of its antiviral inhibition. Another critical residue, His41, was satisfactorily at a distance of 2.89 Ã… from bound LPV ( Figure 3A and 4A). While ATV did not interact with His41 or Cys145 ( Figure S2B and S3B), its position remained stable within the active site independent of conformational changes displayed by the enzyme ( Figure 3B and 4B). The steric occupation of the cleft in the enzymatic active site by ATV, which block the residues of the catalytic amino acids, can be explained by its stronger interactions with Mpro, compared to LPV, through multiple hydrogen bonds during stationary docking and molecular dynamics (Tables S1-S3).