Abstract
African swine fever virus (ASFV) infection is fatal in domesticated pigs, with a mortality rate approaching 100%. This may result in economic losses and threats to food security. Currently, there are no approved vaccines or antiviral therapies for ASFV. Therefore, in this study, we evaluated congocidine congeners and a tris-benzimidazole as potential inhibitors of ASFV transcription using an in silico approach. We applied redocking of congocidine and docking of its congeners and a tris-benzimidazole to a receptor containing B-DNA with AT-motifs as a target to mimic conserved ASFV late gene promoters. Subsequently, the binding scores of DNA-ligand docked complexes were evaluated and their binding affinity was estimated. Molecular dynamics (MD) simulation was then used to assess ligand behavior within the minor groove. From our results, it is evident the less toxic congocidine congeners and tris-benzimidazole could dock to AT-rich regions significantly. Additionally, the predicted binding affinities had suitable values comparable to other experimentally determined minor groove binders, MD simulation of the docked DNA-ligand complexes and subsequent molecular trajectory visualization further showed that the ligands remained embedded in the minor groove during the time course of simulation, indicating that these ligands may have potential applications in abrogating ASFV transcription.
Highlights
DNA is a major target for various types of drugs [1]
The 473D structure was selected based on the fact that d (CGTATATACG) 2 has the K-mer signature motifs TATATA, ATAT, and TATA, which are similar to conserved AT-rich promoter motifs observed in the African swine fever virus (ASFV) genome that are responsible for late gene transcription in ASFV [8,9,10,11]
From the stacked conformers in this study, all of the top five docked poses for minor groove binders had the score (S) less than -32, strongly suggesting that both the congocidine congeners and tris-benzimidazole could significantly bind to the TATATA motifs like congocidine
Summary
DNA is a major target for various types of drugs [1]. Results from the analysis of several highresolution structures suggest that the minor groove of DNA may function as a receptor for proteins and small molecules [2]. Drugs that bind to the minor groove may be exploited when pursuing a subset of viruses that replicate in the cytoplasm, such as the African swine fever (ASF) virus (ASFV). ASFV causes ASF, a fatal disease that affects domestic pigs. ASFV infection can affect the food supply, as pork is one of the most commonly consumed kinds of meat worldwide [3]. There are no vaccines or antiviral drugs approved for use against ASFV [4], and to date, reversible minor groove binders have not been applied or studied in mitigating ASFV
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