In silico design of potent agonists for human PPAR γ

Peroxisome proliferator-activated receptor (PPAR γ) acts as a key regulator on adipocyte differentiation and glucose homeostasis. PPAR γ has been implicated in the pathology of type 2 diabetes. As human PPAR γ activity is considered important in improving insulin sensitivity, in silico screening was carried out to find potent agonists for human PPAR γ protein. The co-crystal structure of PPAR γ, solved through X-Ray diffraction method was retrieved from the protein data bank. Four PPAR γ agonists selected from literature were submitted to subsequent 2D searching protocol using Ligand.Info, which yielded 1699 structural analogs. The PPAR γ co-crystal structure and ligand dataset were preprocessed using protein preparation wizard and LigPrep, respectively. Further, docking was performed by using three phased docking protocol of Maestro v9.2 that implements Glide v5.7. The obtained thirteen leads through docking were compared with the existing inhibitors and seven leads with good binding affinity with PPAR γ were proposed. The binding orientations of the seven leads were coinciding well with the native co-crystal structure of human PPAR γ. Thus, the proposed seven leads can be suggested as potential agonists for improving insulin sensitivity in the treatment of type 2 diabetes mellitus if synthesized and validated in animal model

The structural, functional, and dynamic effect of Tau tubulin kinase1 upon a mutation: A neuro-degenerative hotspot.

AbstractAlzheimer's disease (AD) is a progressive disorder that causes brain cells to degenerate and die. AD is one of the common causes of dementia that leads to a decline in thinking, behavioral and social skills that disrupts a person's ability to function independently. Tau‐tubulin kinase1 (TTBK1) is a crucial disease regulating AD protein, which is majorly responsible for the phosphorylation and accumulation of tau protein at specific Serine/Threonine residues found in paired helical filaments, suggesting its role in tauopathy. TTBK1 involvement in many diseases and the restricted expression of TTBK1 to the central nervous system (CNS) makes TTBK1 an attractive therapeutic target for tauopathies. The genetic variations in TTBK1 are primarily involved in the TTBK1 pathogenesis. This study highlighted the destabilizing, damaging and deleterious effect of the mutation R142Q on TTBK1 structure through computational predictions and molecular dynamics simulations. The protein deviation, fluctuations, conformational dynamics, solvent accessibility, hydrogen bonding, and the residue‐residue mapping confirmed the mutant effect to cause structural aberrations, suggesting overall destabilization due to the protein mutation. The presence of well‐defined free energy minima was observed in TTBK1‐wild type, as opposed to that in the R142Q mutant, reflecting structural deterioration. The overall findings from the study reveal that the presence of R142Q mutation on TTBK1 is responsible for the structural instability, leading to disruption of its biological functions. The mutation could be used as future diagnostic markers in treating AD

Prediction of novel inhibitors for human RNase1 involved in cardiovascular disease through in silico screening

Human pancreatic ribonuclease (RNase1) is a small digestive and pyramidine specific enzyme secreted by the pancreas. RNase1 contributes in the regulation of extracellular RNA by hydrolyzing RNA phosphodiester bonds. High levels of RNase1 in cardiovascular disease patients project the enzyme as an attractive drug target. The known RNase1 inhibitors, citric acid and U1S were searched for structural analogs from Ligand.info database to compile 783 ligands. The ligands' 3D structures and their tautomeric states were generated using LigPrep. The 3424 prepared conformations were subjected to QikProp analysis and filtered based on Lipinski rule of five and zero reactive functional group. The 3376 conformations with good ADME (absorption, desorption, metabolism, excretion) profile were passed through multistage docking in virtual screening workflow of Schrodinger software 2011. Seventy five ligands with good binding affinity towards RNase1 were ranked based on XPGscore, through Glide extra precision (XP) docking. Twenty three ligands with better XPGscore compared to published inhibitors (citric acid and U1S) were proposed as potential RNase1 inhibitors. Analysis of docking complexes, their binding orientations, XPGscores and through stringent correlation with published data lead ‘1’ that showed least XPGscore (-12.284 Kcal/mol) was proposed as the best molecule to consider for rational drug designing for treatment of cardiovascular disease