Molecular docking studies of chloroquine and its derivatives against P23pro‐zbd domain of chikungunya virus: Implication in designing of novel therapeutic strategies. Issue 10 (16th July 2019)

• Record Type: Journal Article
• Authors: Kumar, Maneesh; Topno, Roshan Kamal; Dikhit, Manas Ranjan; Bhawana, ; Sahoo, Ganesh Chandra; Madhukar, Major; Pandey, Krishna; Das, Pradeep
• Is Part Of: Journal of cellular biochemistry. Volume 120:Issue 10(2019)
• Page Start: 18298
• Page End: 18308
• Publication Date: 2019-07-16
• Subjects: chemotherapeutic drug -- chikungunya virus -- didesethyl chloroquine hydroxyacetamide -- domains -- LibDock -- P23pro‐zbd; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.29139
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: The arthropod‐transmitted chikungunya virus has emerged as an epidemic menace that causes debilitating polyarthritis. With this life‐threatening impact on humans, the possible treatment requires to cure the viral infectivity. But, devoid of any vaccine against the chikungunya virus (CHIKV), there is a need to develop a novel chemotherapeutic strategy to treat this noxious infection. CHIKV carries highly compact P23 pro‐zbd structure that possesses potential RNA‐binding surface domains which extremely influences the use of RNA template during genome replication at the time of infection and pathogenesis. Therefore, computational approaches were used to explore the novel small molecule inhibitors targeting P23 pro‐zbd domain. The tertiary structure was modeled and optimized using in silico approaches. The results obtained from PROCHECK (93.1% residues in favored regions), ERRAT (87.480 overall model quality) and ProSA ( Z ‐score: −11.72) revealed the reliability of the proposed model. Interestingly, a previously reported inhibitor, chloroquine possesses good binding affinities with the target domain. In‐depth analysis revealed that chloroquine derivatives such as didesethyl chloroquine hydroxyacetamide, cletoquine, hydroxychloroquine exhibited a better binding affinity. Notably, MD simulation analysis exhibited that Thr1312, Ala1355, Ala1356, Asn1357, Asp1364, Val1366, Cys1367, Ala1401, Gly1403, Ser1443, Tyr1444, Gly1445, Asn1459, and Thr1463 residues are the key amino acid responsible for stable ligand‐protein interaction. The results obtained from this study provide new insights and advances the understanding to develop a new approach to consider effective and novel drug against chikungunya. However, a detailed in vivo study is required to explore its drug likeliness against this life‐threatening disease. Abstract : The amino acid residues Ala1356, Gly1403, and Ser1443 at the active site of the homology model of P23pro‐zbd domain of Chikungunya virus crucially interact with chloroquine derivative compound didesethyl chloroquine hydroxyacetamide.