Homology modeling and virtual screening for antagonists of protease from yellow head virus

Abstract

Yellow head virus (YHV) is one of the causative agents of shrimp viral disease. The prevention of YHV infection in shrimp has been developed by various methods, but it is still insufficient to protect the mass mortality in shrimp. New approaches for the antiviral drug development for viral infection have been focused on the inhibition of several potent viral enzymes, and thus the YHV protease is one of the interesting targets for developing antiviral drugs according to the pivotal roles of the enzyme in an early stage of viral propagation. In this study, a theoretical modeling of the YHV protease was constructed based on the folds of several known crystal structures of other viral proteases, and was subsequently used as a target for virtual screening-molecular docking against approximately 1364 NCI structurally diversity compounds. A complex between the protease and the hit compounds was investigated for intermolecular interactions by molecular dynamics simulations. Five best predicted compounds (NSC122819, NSC345647, NSC319990, NSC50650, and NSC5069) were tested against bacterial expressed YHV. The NSC122819 showed the best inhibitory characteristic among the candidates, while others showed more than 50 % of inhibition in the assay condition. These compounds could potentially be inhibitors for curing YHV infection.

In silico screening of chalcones and flavonoids as potential inhibitors against yellow head virus 3C-like protease

“…Considering the genetic similarity and mactching residue position of 3CL pro H63 and C152 in the catalytic dyad of both GAV and YHV 3CL pro ( Fig. 1A ), we identified H63 as one of the catalytic residues in our model instead of the previously proposed H30 ( Unajak et al, 2014 ). The designation of H63 as part of the YHV 3CL pro catalytic dyad is in great accordance with the previous experimental reports ( Ziebuhr et al, 2003 ).…”

“…Thus, the model YHV_M2 was chosen to be a representative model for YHV 3CL pro in the following studies. The previous homology based model of YHV 3CL pro suggested H30, D70, and C152 as 3 catalytic residues that form the catalytic triad of the protease ( Unajak et al, 2014 ). On the contrary, our predicted model from AlphaFold2 indicated that the YHV 3CL pro employs H-C catalytic dyad for proteolytic mechanism which is in good agreement with the previous experimental data obtained from GAV 3CL pro ( Ziebuhr et al, 2003 ).…”

“…Molecular docking with 100 runs was employed to generate the possible ligand binding configurations in the binding pocket of YHV and GAV 3CL pro . For each compound, the best configuration with lowest binding free energy (ΔG) was chosen to be ranked and compared with the known YHV inhibitor, NSC122819 ( Unajak et al, 2014 ). The ΔG of NSC122819 was of −8.0 kcal/mol in YHV 3CL pro and −6.7 kcal/mol in GAV 3CL pro .…”

“…According to previous works about potentials of flavonoid and chalcone as viral protease inhibitors , HIV-1 protease ( Turkovic et al, 2020 ; Xu et al, 2000 ), dengue-2 protease ( Hengphasatporn et al, 2020 ; Kiat et al, 2006 ; Srivarangkul et al, 2018 ), MERS-CoV 3CL pro ( Jo et al, 2019 ), and SARs-CoV 3CL pro ( Hengphasatporn et al., 2022 ; Nguyen et al, 2012 ; Park et al, 2016 ), as well as their low toxicity and bioavailable nature, the set of 223 chalcones and 49 flavonoids from in-house database ( Sangpheak et al, 2019 ) was considered for identification of bioactive drug candidates for inhibition of YHV major protease, YHV 3CL pro , in this study. The structure of the reported anti-YHV 3CL pro agent, NSC122819 ( Unajak et al, 2014 ), was downloaded from the ZINC database. The 2D structures of all studied compounds were depicted in supplemental Fig.…”

“…3CL pro plays a pivotal role in the viral replication process by cleaving the viral polyproteins at multiple conserved sites to release several vital replicative proteins ( Ziebuhr et al, 2003 ). Due to the unavailability of the 3D structure from X-ray crystallography, nuclear magnetic resonance (NMR), or cryogenic electron microscopy (cryo-EM) of YHV 3CL pro , homology-based modeling has been conducted to gain the structural basis of this viral protease ( Unajak et al, 2014 ). The YHV 3CL pro model was used in virtual screening for potential compounds from the cancer therapeutic drugs database.…”