Design Novel Dual Agonists for Treating Type-2 Diabetes by Targeting Peroxisome Proliferator-Activated Receptors with Core Hopping Approach

Abstract

Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors) have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful “core hopping” and “glide docking” techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the “core hopping” technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses.

Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2

“…In order to gain high binding affinity inhibitors of PTP1B over SHP-2, the program for Core-Hopping [36,37] in Schrodinger suite 2009 was utilized in this study that has the function to perform both the fragment-based replacing and molecular docking. During the process of core-hopping, the point was defined in advance for scaffold replacement in the Define Combinations Step from the Combinatorial Screening panel.…”

Identification of Glucose-Binding Pockets in Human Serum Albumin Using Support Vector Machine and Molecular Dynamics Simulations

“…Computational docking operation is a useful vehicle for investigating the interaction of a protein receptor with its ligand and revealing their binding mechanism as demonstrated by a series of studies [28,[86][87][88][89][90][91][92][93][94][95]. Here, we chose representative snapshots of the cryptic pockets (3 and 30), lysine-containing pockets (7 and 9) and arginine-containing pockets (13, 20 and 26) and docked it with glucose.…”

Molecular Recognition of Human Angiotensin-Coverting Enzyme I (hACE I) and Different Inhibitors

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