Abstract
Objective: APOBEC3B (A3B) enzyme causes C-to-T or C-to-G somatic alteration in the cancer genome, leading to the evolution of a broad spectrum of human cancers. The present study aims to identify A3B small molecule inhibitors using a top-down approach via pharmacoinformatic virtual screening.
 Methods: Virtual screening of 2951 drug-alike molecules with diversified structures from the National Cancer Institute Development Therapeutics Program (DTP-NCI) compounds library was performed using GOLD and AutoDock Vina docking programs against the 3D structure of A3B (PDB ID: 5TD5).
 Results: Amongst the docked compounds, Nordracorubin, NSC641233 and Raloxifene hydrochloride showed the most potent binding affinities towards A3B on both Autodock/Vina and GOLD. Several significant similarities were observed between A3B and the three hits, including hydrogen bonds and pi-pi stacking. The three compounds also exhibited interaction with the centralized zinc cofactor and amino acid residues that directly contribute the deaminase activity of A3B enzyme.
 Conclusion: We hypothesize that the findings from this study could significantly shorten the quest for novel molecules against the A3B after confirmation with subsequent in vitro and in vivo studies in the near future.
Highlights
The APOBEC ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like") in human is part of a broader superfamily of zincdependent cytidine deaminase enzymes that consists of 11 family members, including APOBEC1, activation-induced deaminase (AID), APOBEC1, APOBEC2, APOBEC3 subunits, and APOBEC4
The DTP-NCI data set we used in the current study includes Approved Oncology Drugs Set with 166 compounds; Diversity Set VI with 1584 compounds; Mechanistic Set V with 811 compounds, and; Natural Products Set V with 390 compounds
This study discovered three prospective inhibitory compounds against A3B enzyme activity using Autodock/Vina, and Genetic optimization for ligand docking (GOLD)
Summary
The APOBEC ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like") in human is part of a broader superfamily of zincdependent cytidine deaminase enzymes that consists of 11 family members, including APOBEC1, activation-induced deaminase (AID), APOBEC1, APOBEC2, APOBEC3 subunits, and APOBEC4. These proteins remove the 4-NH2 group from cytosines/cytidines on single-stranded (ssDNA) or RNA and convert them into uracils (C-toU conversion). The core structure of A3B is supported by a backbone of five β-sheet strands and six α-helices motifs with a centralized zinc ion. Upon binding to the ssDNA, the substrate target cytosine will be inserted deep into the A3B active binding cavity containing a zinc ion and amino acid residues of Cys101, Cys106, and His253 [2]
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