Abstract
Chikungunya virus (CHIKV) a re-emerging mosquito-borne alpha virus causes significant distress which is further accentuated in the lack of specific therapeutics or a preventive vaccine, mandating accelerated research for anti-CHIKV therapeutics. In recent years, drug repositioning has gained recognition for the curative interventions for its cost and time efficacy. CHIKV envelope proteins are considered to be the promising targets for drug discovery because of their essential role in viral attachment and entry in the host cells. In the current study, we propose structure-based virtual screening of drug molecule on the crystal structure of mature Chikungunya envelope protein (PDB 3N41) using a library of FDA approved drug molecules. Several cephalosporin drugs docked successfully within two binding sites prepared at E1-E2 interface of CHIKV envelop protein complex with significantly low binding energies. Cefmenoxime, ceforanide, cefotetan, cefonicid sodium and cefpiramide were identified as top leads with a cumulative score of -67.67, -64.90, -63.78, -61.99, and - 61.77, forming electrostatic, hydrogen and hydrophobic bonds within both the binding sites. These shortlisted leads could be potential inhibitors of E1-E2 hetero dimer in CHIKV, hence might disrupt the integrity of envelope glycoprotein leading to loss of its ability to form mature viral particles and gain entry into the host.
Highlights
Chikungunya virus (CHIKV), a mosquito-borne alphavirus, transmitted through Aedes aegypti and Aedes albopictus has become a global threat causing recurrent epidemic
In this study we propose, structure-based virtual screening of drug molecules currently used as the cell envelop inhibitors of bacteria, on the 3-D structure of mature envelope glycoproteins E1 and E2 of CHIKV with the aim to delineate potential novel inhibitors to restrict CHIKV entry into the host cells and to inhibit viral assembly
Though two forms of CHIKV envelope glycoproteins are seen in the cells, i.e. mature and immature and in this study we have chosen the mature envelope glycoprotein complex because it is present on the virion surface in the mature form
Summary
Chikungunya virus (CHIKV), a mosquito-borne alphavirus, transmitted through Aedes aegypti and Aedes albopictus has become a global threat causing recurrent epidemic. With its first outbreak reported from Makonde, Tanzania in 1952, [1] it largely remained restricted to Africa and Asia, but in last few years, a large number of epidemic were recorded from America as well as Europe [2]. The word chikungunya means “to walk bent over” in the Makonde language of Africa in reference to the stooped posture acquired due to incapacitating arthralgia [4], that persist for months after acute infection is over. CHIKV contains single-stranded, positive-sense RNA genome (11.8 Kb), with two open reading frames (ORFs). The 5’ ORF encodes four non-structural proteins nsP 1-4, whereas the 3’ORF
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