title: Discovery of Novel Peptidomimetics as Irreversible CHIKV NsP2 Protease Inhibitors Using Quantum Mechanical-Based Ligand Descriptors.
abstract: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus. Recent outbreaks of CHIKV infections have been reported in Asia, Africa, and Europe. 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 EC90 of 8.76-9.57 μg/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 nsP2 protease leading to permanent enzyme inactivation via Michael 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 Lipinski 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
authors.forename: Eman M
authors.initials: EM
authors.lastname: El-labbad
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
authors.forename: Mohammed A H
authors.initials: MA
authors.lastname: Ismail
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
authors.forename: Dalal A
authors.initials: DA
authors.lastname: Abou Ei Ella
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Marawan
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Molecular Model Discovery Laboratory, Department of Chemistry and Biotechnology, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Melbourne, Vic., 3122, Australia.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.|LiKaShing Institute of Virology, University of Alberta, Edmonton, AB, Canada.|LiKaShing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Khaled H
authors.initials: KH
authors.lastname: Barakat
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
authors.forename: Khaled A M
authors.initials: KA
authors.lastname: Abouzid
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D065632:Chikungunya Fever / Q000188:drug therapy; D002646:Chikungunya virus / Q000187:drug effects* / Q000201:enzymology*; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D007408:Intestinal Absorption; D008024:Ligands; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011789:Quantum Theory; D012995:Solubility; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D057786:Peptidomimetics; D011480:Protease Inhibitors
keywords: Chikungunya virus; admet; atomic condensed Fukui functions; covalent docking; lowest unoccupied molecular orbital energies; peptidomimetics