Target specificity of selective bioactive compounds in blocking α-dystroglycan receptor to suppress Lassa virus infection: an <i>in</i> <i>silico</i> approach

Abstract

Lassa hemorrhagic fever, caused by Lassa mammarenavirus (LASV) infection, accumulates up to 5000 deaths every year. Currently, there is no vaccine available to combat this disease. In this study, a library of 200 bioactive compounds was virtually screened to study their drug-likeness with the capacity to block the α-dystroglycan (α-DG) receptor and prevent LASV influx. Following rigorous absorption, distribution, metabolism, and excretion (ADME) and quantitative structure-activity relationship (QSAR) profiling, molecular docking was conducted with the top ligands against the α-DG receptor. The compounds chrysin, reticuline, and 3-caffeoylshikimic acid emerged as the top three ligands in terms of binding affinity. Post-docking analysis revealed that interactions with Arg76, Asn224, Ser259, and Lys302 amino acid residues of the receptor protein were important for the optimum binding affinity of ligands. Molecular dynamics simulation was performed comprehensively to study the stability of the protein-ligand complexes. In-depth assessment of root-mean-square deviation (RMSD), root mean square fluctuation (RMSF), polar surface area (PSA), B-Factor, radius of gyration (Rg), solvent accessible surface area (SASA), and molecular surface area (MolSA) values of the protein-ligand complexes affirmed that the candidates with the best binding affinity formed the most stable protein-ligand complexes. To authenticate the potentialities of the ligands as target-specific drugs, an in vivo study is underway in real time as the continuation of the research.

Point-specific interactions of isovitexin with the neighboring amino acid residues of the hACE2 receptor as a targeted therapeutic agent in suppressing the SARS-CoV-2 influx mechanism

“…In the quantitative observation, eight binding pockets were estimated for the hACE2 receptor protein, obtained from the COACH-D algorithm [ 22 , 23 ]. After evaluating the predicted binding energy and involvement of particular residues, the top binding pockets were chosen from the eight found ( Fig.…”

“…The pharmacokinetic properties of isovitexin following its absorption, distribution, metabolism, elimination, and toxicity (ADMET) and quantitative structure–activity relationship (QSAR) profiles were studied [ 24 ]. The parameters that followed Lipinski’s rule were initially evaluated using Swiss ADME and Molinspiration Cheminformatics [ 22 ]. Finally, the toxicity level was analyzed using the pkCSM server system [ 23 ].…”

Metformin, empagliflozin and their combination modulate ex-vivo macrophage inflammatory gene expression

“…A high resolution (2.4 Å) 3D crystal structure of TLR2 (PDB ID: 3A7C) was selected from the protein data bank (Berman et al 2003) and converted to PDB format. This structure was then processed to present the proper size, orientation, and rotations of the protein (Arefin et al 2021). The processing was carried out in UCSF Chimera (version 1.14) (https://www.cgl.ucsf.edu/chimera/) to remove non-standard amino acids, water molecules, ligands and ions, add missing hydrogen atoms, and to perform energy minimization of the protein structure (Yang et al 2012).…”

Investigating the Anticancer Potential of Salvicine as a Modulator of Topoisomerase II and ROS Signaling Cascade

“…Salvicine-induced DNA DSBs activate ATM and ATR kinases, as well as histone H2AX phosphorylation, in A549 lung cancer cells, which has been widely described in DSB-induced cellular responses ( 149 , 150 ). Salvicine inhibits the catalytic subunit of DNA-dependent protein kinase (DNA-PK), but not the Ku70 or Ku86 subunits, which is surprising.…”