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Discovery of Novel Peptidomimetics as Irreversible CHIKV Ns P 2 Protease Inhibitors Using Quantum Mechanical‐Based Ligand Descriptors
Author(s) -
Ellabbad Eman M.,
Ismail Mohammed A. H.,
Abou Ei Ella Dalal A.,
Ahmed Marawan,
Wang Feng,
Barakat Khaled H.,
Abouzid Khaled A. M.
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12621
Subject(s) - peptidomimetic , lipinski's rule of five , chemistry , chikungunya , protease , docking (animal) , stereochemistry , alphavirus , combinatorial chemistry , virology , virus , biochemistry , enzyme , biology , medicine , peptide , nursing , in silico , gene
Chikungunya virus ( CHIKV ) is a mosquito‐borne alphavirus. Recent outbreaks of CHIKV infections have been reported in A sia, A frica, and E urope. The symptoms of CHIKV infection include fever, headache, nausea, vomiting, myalgia, rash, and 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, and antiviral activity screening of new topographical peptidomimetics revealed three potential prototype agents 3a , 4b, and 5d showing 93–100% maximum inhibition of CHIKV replication in cell‐based assay having EC 90 of 8.76–9.57 μ g/mL. Intensive molecular modeling studies including covalent docking, lowest unoccupied molecular orbital energies, and the atomic condensed Fukui functions calculations strongly suggested the covalent binding of peptidomimetics 3a , 4b, and 5d to CHIKV ns P 2 protease leading to permanent enzyme inactivation via M ichael adduct formation between α / β ‐unsaturated ketone functionality in our designed peptidomimetics and active site catalytic cysteine1013. Furthermore, small molecular weight peptidomimetics 3a and 4b satisfied the L ipinski rule of five for drug‐likeness and showed promising intestinal absorption and aqueous solubility via computational admet studies making them promising hits for further optimization.