ABSTRACT
The genetic alteration in the antioxidant gene Glutathione-S-Transferases Pi 1 (GSTP1) namely GSTP1*IIe105Val (rs1695) and GSTP1*Ala114Val (rs1138272) changes the individual susceptibility to cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) by altering the substrate binding and catalytic activity. This study aims to investigate the association of GSTP1 rs1695 and rs1138272 polymorphism with CVD development in T2DM patients. Genotyping was performed with 400 study participants-group I: control; group II: T2DM; group III: CVD; and group IV: T2DM/CVD [n = 100 each] by PCR-RFLP. The rs1695 and rs1138272 polymorphism were docked against NPACT and NUBBE database and virtually screened using glide. The study reported that rs1695 polymorphism was associated with T2DM risk under dominant and allelic genetic models [OR = 1.97(1.08-3.59) p = 0.02 and OR = 1.79(1.20-2.66) p = 0.003, respectively]. The val/val genotype, dominant, recessive model, and T allelic genetic model were associated with increased CVD risk [OR = 4.15(1.97-8.73) p = < 0.01; OR = 3.16(1.65-6.04) p = < 0.01; OR = 3.47(1.91-6.31) p = < 0.01; and OR = 2.94(1.95-4.43) p = < 0.01, respectively]. In contrast, rs1695 polymorphism was not associated with CVD development among patients with T2DM. In rs1138272, the wild genotype was only detected and neither heterozygous nor val/val genotype was observed. The docking analysis revealed that the Ile105Val mutation plays a significant role in altering the GSTP1 capacity compared to the Ala115Val mutation. This suggests that the Ile105Val mutation has a greater impact on the protein's structure, function, or susceptibility to diseases compared to the Ala115Val mutation. In summary, genetic alteration in GSTP1 rs1695 potentially contributes to an increased risk of T2DM and CVD.
ABSTRACT
The renin enzyme is considered a promising target for hypertension and renal diseases. Over the last three decades, several experimental and theoretical studies have been engaged in the discovery of potent renin inhibitors. The identified inhibitors that undergo clinical trials are still failing to meet the criteria of potency and safety. To date, there is no specific FDA-approved drug for renin inhibition. Our theoretical opinion describes that the most potent compounds identified in experimental studies but lacking safety and overdose issues could be solved by finding similar molecules that are stable, very active, and have no side effects, which will kick start the drug discovery process. Here, we utilized the most potent direct renin inhibitors reported earlier, followed further by our theoretical study reported in 2019. Ligand-based virtual screening, density functional theory, and dynamic simulation studies were employed to explore the identified compounds and co-crystallized molecule in the protein structure. From the diverse databases, we have identified several identical molecules based on their structural features, such as functional groups like hydrophobic (H), aromatic rings (R), hydrogen bond acceptor (A), and donor (D). The HHHPR five-point pharmacophore feature was identified as a template pharmacophore to search the potential compounds from the Enamine and LifeChemical databases and have a good fitness score with known renin inhibitors. Furthermore, theoretical validation was done through several studies that confirmed the activity of the identified molecules. Overall, we propose that these compounds might break the failure in adverse events and improve the potency of hypertension treatment.Communicated by Ramaswamy H. Sarma.
