Virtual screening of inhibitors against Envelope glycoprotein of Chikungunya Virus: a drug repositioning approach

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.

Promising inhibitors of main protease of novel corona virus to prevent the spread of COVID-19 using docking and molecular dynamics simulation

“…Trajectories analyses were performed using the CPPTRAJ modules (Roe & Cheatham, 2013. Authors analyzed different trajectories like root mean square deviation (RMSD), a root mean square fluctuation (RMSF), hydrogen bonds (HBs) obtained from the MD simulation along with the change in binding free energy calculation using the AMBER18 (Agarwal et al, 2019;Al-Refaei et al, 2020;Cob-Calan et al, 2019;Nazarian et al, 2015;Pola et al, 2018).…”

Computer-Aided Design, Synthesis, and Antiviral Evaluation of Novel Acrylamides as Potential Inhibitors of E3-E2-E1 Glycoproteins Complex from Chikungunya Virus

“…Still, it hydrophobically interacts with Leu 42 , Val 179 , Tyr 180 , Asn 264 , Pro 265 , and Val 266 , while also interacting with Ser 120 and Tyr 122 amino acids, via hydrogen bonding interactions at distances of 2.07 and 2.1 Å, respectively ( Figure 9 C). Additionally, in silico studies involving E3-E2-E1 glycoproteins have been developed focusing on virtual screening of phenothiazines, bafilomycin [ 85 ], and FAD-approved antimicrobial agents, such as cefmenoxime, ceforanide, cefotetan, cefonicid sodium, and cefpiramide [ 86 ]. Recently, Song et al (2019) [ 87 ] reported the crystal structures of the free mouse MXRA8 (mMXR8) receptor and the complex between human MXRA8 (hMXRA8) and the CHIKV E3-E2-E1 glycoproteins complex.…”

Antiviral therapeutics for chikungunya virus

“…The repurposing of several molecules/inhibitors has been reported like chloroquine (antimalarial drug), ribavirin, suramin, T-705, arbidol, chlorpromazine, imipramine, piperazine, and cephalosporin (anti-bacterial) to inhibit CHIKV [53][54][55]. Similarly, mycophenolic acid which is an immunosuppressant and anti-proliferative molecule can be repurposed for CHIKV as it can control 99.9% viral replication at a concentration of 10 μM [16].…”

“…Recently, Kumar et al exploited molecular docking and dynamic simulation studies and reported ribostamycin sulfate as an inhibitor of CHIKV nsP2 protease [59]. Moreover, Agarwal et al reported cephalosporin drugs targeting CHIKV E1-E2 proteins using drug repurposing and in silico approaches [53].…”