Discovery of novel peptidomimetics as irreversible CHIKV nsP2 protease inhibitors using quantum mechanical-based ligand descriptors
Autor(es): El-Labbad Eman M, Ismail Mohammed A H, Abou Ei Ella Dalal A, Ahmed Marawan, Wang Feng, Barakat Khaled H, Abouzid Khaled A M
Resumo: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus. Recent outbreaks of CHIKV infections have been reported in Asia, Africa, - Europe. The symptoms of CHIKV infection include fever, headache, nausea, vomiting, myalgia, rash, - chronic persistent arthralgia. To date, no vaccines or selective antiviral drugs against this important emerging virus have been reported. In this study, the design, synthesis, - antiviral activity screening of new topographical peptidomimetics revealed three potential prototype agents 3a, 4b, - 5d showing 93-100% maximum inhibition of CHIKV replication in cell-based assay having EC90 of 8.76-9.57 ?g/mL. Intensive molecular modeling studies including covalent docking, lowest unoccupied molecular orbital energies, - the atomic condensed Fukui functions calculations strongly suggested the covalent binding of peptidomimetics 3a, 4b, - 5d to CHIKV nsP2 protease leading to permanent enzyme inactivation via Michael adduct formation between ?/?-unsaturated ketone functionality in our designed peptidomimetics - active site catalytic cysteine1013. Furthermore, small molecular weight peptidomimetics 3a - 4b satisfied the Lipinski rule of five for drug-likeness - showed promising intestinal absorption - aqueous solubility via computational admet studies making them promising hits for further optimization.
Palavras-Chave: Chikungunya virus; Admet; Atomic condensed Fukui functions; Covalent docking; Lowest unoccupied molecular orbital energies; Peptidomimetics
Imprenta: Chemical Biology & Drug Design, v. 86, n. 6, p. 1518-1527, 2015
Identificador do objeto digital: 10.1111/cbdd.12621
Descritores: Chikungunya virus - Cell ; Chikungunya Virus - Virus ; Chikungunya virus - Molecular screening ; Chikungunya virus - Vaccine ; Chikungunya virus - Chikungunya fever
Data de publicação: 2015
