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Deprecated: Implicit conversion from float 298.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 ACS+Cent+Sci 2021 ; 7 (3): 467-475 Nephropedia Template TP
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Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations #MMPMID33786375
Zhang CH; Stone EA; Deshmukh M; Ippolito JA; Ghahremanpour MM; Tirado-Rives J; Spasov KA; Zhang S; Takeo Y; Kudalkar SN; Liang Z; Isaacs F; Lindenbach B; Miller SJ; Anderson KS; Jorgensen WL
ACS Cent Sci 2021[Mar]; 7 (3): 467-475 PMID33786375show ga
Starting from our previous finding of 14 known drugs as inhibitors of the main protease (M(pro)) of SARS-CoV-2, the virus responsible for COVID-19, we have redesigned the weak hit perampanel to yield multiple noncovalent, nonpeptidic inhibitors with ca. 20 nM IC(50) values in a kinetic assay. Free-energy perturbation (FEP) calculations for M(pro)-ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered the potent analogues. The design efforts were confirmed and augmented by determination of high-resolution X-ray crystal structures for five analogues bound to M(pro). Results of cell-based antiviral assays further demonstrated the potential of the compounds for treatment of COVID-19. In addition to the possible therapeutic significance, the work clearly demonstrates the power of computational chemistry for drug discovery, especially FEP-guided lead optimization.