Genetic insights into obesity: <i>in silico</i> identification of pathogenic SNPs in <i>MBOAT4</i> gene and their structural molecular dynamics consequences

Membrane Bound O-Acyltransferase Domain-Containing 4 (MBOAT4) protein catalyzes ghrelin acylation, leading to prominent ghrelin activity, hence characterizing its role as an anti-obesity target. We extracted 625 exonic SNPs from the ENSEMBL database and one phenotype-based missense mutation associated with obesity (A46T) from the HGMD (Human Gene Mutation Database). These were differentiated on deleterious missense SNPs of the <i>MBOAT4</i> gene through MAF (minor allele frequency: &lt;0.01) cut-off criteria in relation to some bioinformatics-based supervised machine learning tools. We found 8 rare-coding and harmful missense SNPs. The consensus classifier (<i>PredictSNP</i>) tool predicted that the SNP (G57S, C: rs561065025) was the most pathogenic. Several trained <i>in silico</i> algorithms have predicted decreased protein stability [ΔΔG (kcal/mol)] function in the presence of these rare-coding pathogenic mutations in the <i>MBOAT4</i> gene. Then, a stereochemical quality check (i.e. validation and assessment) of the 3D model was performed, followed by a blind cavity docking approach, used to search for druggable cavities and molecular interactions with citrus flavonoids of the <i>Rutaceae</i> family, ranked with energetic estimations. Significant interactions with <i>Phloretin 3',5'-Di-C-Glucoside</i> were also observed at R304, W306, N307, A311, L314 and H338 with (iGEMDOCK: −95.82 kcal/mol and AutoDock: −7.80 kcal/mol). The RMSD values and other variables of MD simulation analyses on this protein further validated its significant interactions with the above flavonoids. The <i>MBOAT4</i> gene and its molecular interactions could serve as an interventional future anti-obesity target. The current study’s findings will benefit future prospects for large population-based studies and drug development, particularly for generating personalized medicine. Communicated by Ramaswamy H. Sarma