INTEGRATED IN SILICO AND MOLECULAR DOCKING ANALYSIS OF GDF7 nsSNPs ASSOCIATED WITH BARRETT’S ESOPHAGUS

R BIBI, S RIAZ, S KHAN, R SALMANOVA, MZ SADIKAN, S MOEEZ, S KIRBAG, Q ALI, A ULLAH

Growth differentiation factor 7 (GDF7), a member of the transforming growth factor-β superfamily, plays a vital role in cell differentiation, survival, and development. Mutations in GDF7 have been linked to various disorders, including Barrett’s esophagus (BE), a condition arising from chronic gastroesophageal reflux disease (GERD). This study aimed to evaluate the impact of non-synonymous single nucleotide polymorphisms (nsSNPs) on the structure, stability, and function of the GDF7 protein and to assess the binding potential of proflavine with both wild-type and mutant GDF7 proteins. Missense SNPs were analyzed using SIFT, MUpro, PolyPhen-2, PhD-SNP, GeneMANIA, Meta-SNP, I-mutant, Consurf, Project Hope and SNPs&GO. The wild-type structure of GDF7 was predicted using the AlphaFold database, while mutant models were generated using Swiss Model. Binding sites of GDF7 were predicted using COACH-D, and molecular docking with Proflavine was conducted using AutoDock Vina via PyRx. A total of 325 missense SNPs were found in the GDF7 gene, of which five nsSNPs (rs146317060, rs146567848, rs367794645, rs369544272, rs377143734) were specified as damaging to the structure, stabilization, and role of the GDF7 protein and were housed in conserved regions. The selected 5 mutations (D364H, R419H, K352T, V434A, I423M) were incorporated in the modeling of the mutant structure and template Q9BDW8.1.A model from SWISS-MODEL was selected as most suitable, with 94.63% identity with the amino acid sequence provided. Docking score and interaction analysis showed that Proflavine has strong binding affinity and a variety of interactions with mutated GDF7, so this suggests that the compound has promising potential and can be further developed as a drug for targeting diseases caused by mutations in the GDF7 pathway, when coupled with experimental results in vitro. This study identified 5 harmful nsSNPs in GDF7 and revealed Proflavine as a potential therapeutic molecule for targeting Barrett's Esophagus. The findings provide insights into personalized medicine approaches for managing diseases influenced by GDF7 alterations.