RESUMEN
Hypercholesterolemia is a mediator for the etiology of cardiovascular diseases, which are characterized as the global leading cause of mortality. We aimed to investigate the inhibitory activity of Withania coagulans compounds against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) of Mus musculus using an extensive in silico approach. The 3D structure of the Hmgcr protein is not yet known, so we performed the homology modeling using MODELLER and SWISS-MODEL tools, followed with structural validation and assessment. The PROCHECK web server showed that the top-ranked homology model from SWISS-MODEL has 93.4% of residues in the most-favorable region, the quality factor was 98%, and the Verify3D score was 91.43%, compared to the other generated models. The druggable protein-binding cavities in a 3D model of Hmgcr were investigated with the aid of commonly prescribed statin compounds using the CB-dock approach. We compiled a 3D compound library of W. coagulans, followed by drug-likeness evaluation, and found 20 eligible compounds. The pattern of consensus residues obtained from the CB-dock procedure was then used for grid-box docking of W. coagulans compounds and statin drugs using AutoDock 4.2, respectively. The results showed that withanolide R (-10.77 kcal/mol), withanolide Q (-10.56 kcal/mol), withanolide J (-10.52 kcal/mol), atorvastatin (-8.99 kcal/mol), simvastatin (-8.66 kcal/mol), and rosuvastatin (-8.58 kcal/mol) were promising candidates that bind Hmgcr protein. The key residues involved in protein-ligand (withanolide R) interactions were Y516, C526, V529, I530, M533, I535, and V537, and the formation of a H-bond was at C526, M533, and I535 residues. M533 was the consensus residue having a tendency to form a H-bond with withanolide Q, too. Molecular dynamics simulations were used to validate the top-ranked docked complexes for the stability of the modeled protein. We also predicted the pharmacokinetic properties of binding affinity-based top-ranked compounds and concluded that they could be used as potential inhibitors of Hmgcr. However, further in vitro and in vivo studies are essential to completing the drug development process.
RESUMEN
eart failure is a progressive, chronic disorder. Insulin resistance (IR) has been more and more involved as a preliminary metabolic perturbance predisposing to hyperglycemia, hyperlipidemia and atherosclerosis with others heart diseases. To investigate the relation of insulin resistance (IR) in non-diabetic heart failure patients this case-control study was carried out to ascertain the presence of IR with the aid of Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in non-diabetic heart failure patients (NDHF patients) compared with healthy controls. The sample size was calculated for both, cases (NDHF patients) and control (healthy subjects), which was initially consisted of 113 respondents each. The study consisted of two phase duration. In Phase I, NDHF patients were approached initially; only 80 patients with NDHF completed the study procedure. In Phase II, 80 healthy subjects were targeted and matched. Fasting blood glucose level (FBGL) and serum insulin was estimated. Mathematical model to quantify ß-cell function and insulin resistance was also computed through Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in both groups. Data was analyzed on SPSS version 16. Mean values with ± standard deviation (SD) of insulin (10.2±4.36) and HOMA-IR (2.52±1.15) were significantly (p<0.05) higher in NDHF patients as compared to control subject (6.4±3.39, 1.45±0.80). Average insulin to glucose ratio was 0.10±0.044 in NDHF patients which was significantly (p<0.0001) lowered in controls i.e., 0.073±0.039. Marginal and matrix plot analysis revealed that a higher patients count have had the HOMA-IR values <1.5 units while opposite scenario was observed in control group. Regression analyses of HOMA-IR with FBGL (as independent indicator) also authenticate the similar pattern. The present study concludes that insulin resistance (decreased insulin sensitivity) is a characteristic finding in Pakistani population of heart failure as compared to matched healthy controls.
