scholarly journals Anti-diabetic drug discovery using bioactive compounds: Molecular docking insights

2021 ◽  
Vol 14 (3) ◽  
pp. 075-0178
Author(s):  
John Oluwafemi Teibo ◽  
Samuel Abidemi Bello ◽  
Oluwaseun Abraham Adebisi ◽  
Jeremiah Olorunjuwon Olugbami ◽  
Titilade Kehinde Ayandeyi
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
Bioactive Compounds ◽  
Binding Free Energy ◽  
Tyrosine Phosphatase ◽  
Peroxisome Proliferator ◽  
Protein Database ◽  
Peroxisome Proliferator Activated Receptor ◽  
Starting Point ◽  
Ptp 1B

Diabetes mellitus is a metabolic disorder that has become a global health problem. About 500 million people were estimated to be living with diabetes in 2018 with about 20 million in Africa and 2 million cases in Nigeria. Bioactive compounds offer an advanced starting point in the search for highly specific and potent modulator of bimolecular function as well as novel drugs, which can be studied with more precision by using computer aided drug design (CADD). Molecular docking employed for predicting the interactions between receptor and ligands is an integral aspect in drug discovery. The main objective is to attain ligand-receptor complex with optimized conformation and with the intention of possessing less binding free energy. Several studies have used this method to explore the potency of bioactive compounds to predict better alternatives in the search for an anti-diabetic drug with very effective therapeutic role and minimal side effects. This has been carried out by using several compounds such as Quercetin, against endogenous targets such as Glycogen phosphorylase, Peroxisome Proliferator-activated Receptor (PPAR)-y, Glucokinase, Protein Tyrosine Phosphatase 1-beta (PTP-1B), GLUT4, etc. In Silico tools such as Protein Database (PDB), GenBank and softwares such as Autodock and modeller are of major importance to these studies. The paper seeks to examine bioactive compounds basically quercetin that have been successfully identified through molecular docking and their molecular targets as well as recent advances in the use of molecular docking in the novel discovery and explanation of mechanisms of actions of some bioactive compounds in anti-diabetic drug discovery.

Discovery of an Unexpected Similarity in Ligand Binding Between BRD4 and PPARγ

2019 ◽  
Author(s):  
Lina Humbeck ◽  
Jette Pretzel ◽  
Saskia Spitzer ◽  
Oliver Koch
Keyword(s):  
Cancer Therapy ◽  
Drug Targets ◽  
Synergistic Effects ◽  
Complex Structure ◽  
Peroxisome Proliferator ◽  
Resistance Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Starting Point ◽  
Fundamental Research ◽  
Important Drug

Knowledge about interrelationships between different proteins is crucial in fundamental research for the elucidation of protein networks and pathways. Furthermore, it is especially critical in chemical biology to identify further key regulators of a disease and to take advantage of polypharmacology effects. A comprehensive scaffold-based analysis uncovered an unexpected relationship between bromodomain-containing protein 4 (BRD4) and peroxisome-proliferator activated receptor gamma (PPARγ). They are both important drug targets for cancer therapy and many more important diseases. Both proteins share binding site similarities near a common hydrophobic subpocket which should allow the design of a polypharmacology-based ligand targeting both proteins. Such a dual-BRD4-PPARγ-modulator could show synergistic effects with a higher efficacy or delayed resistance development in, for example, cancer therapy. Thereon, a complex structure of sulfasalazine was obtained that involves two bromodomains and could be a potential starting point for the design of a bivalent BRD4 inhibitor.

scholarly journals The Demethoxy Derivatives of Curcumin Exhibit Greater Differentiation Suppression in 3T3-L1 Adipocytes Than Curcumin: A Mechanistic Study of Adipogenesis and Molecular Docking

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1025
Author(s):  
Ahmed Alalaiwe ◽  
Jia-You Fang ◽  
Hsien-Ju Lee ◽  
Chun-Hui Chiu ◽  
Ching-Yun Hsu
Keyword(s):  
Molecular Docking ◽  
Fatty Acid Synthase ◽  
Structural Similarity ◽  
Mechanistic Study ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Enhancer Binding Protein ◽  
Underlying Mechanisms ◽  
Amp Activated Protein Kinase

Curcumin is a known anti-adipogenic agent for alleviating obesity and related disorders. Comprehensive comparisons of the anti-adipogenic activity of curcumin with other curcuminoids is minimal. This study compared adipogenesis inhibition with curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), and their underlying mechanisms. We differentiated 3T3-L1 cells in the presence of curcuminoids, to determine lipid accumulation and triglyceride (TG) production. The expression of adipogenic transcription factors and lipogenic proteins was analyzed by Western blot. A significant reduction in Oil red O (ORO) staining was observed in the cells treated with curcuminoids at 20 μM. Inhibition was increased in the order of curcumin < DMC < BDMC. A similar trend was observed in the detection of intracellular TG. Curcuminoids suppressed differentiation by downregulating the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), leading to the downregulation of the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). AMP-activated protein kinase α (AMPKα) phosphorylation was also activated by BDMC. Curcuminoids reduced the release of proinflammatory cytokines and leptin in 3T3-L1 cells in a dose-dependent manner, with BDMC showing the greatest potency. BDMC at 20 μM significantly decreased leptin by 72% compared with differentiated controls. Molecular docking computation indicated that curcuminoids, despite having structural similarity, had different interaction positions to PPARγ, C/EBPα, and ACC. The docking profiles suggested a possible interaction of curcuminoids with C/EBPα and ACC, to directly inhibit their expression.

scholarly journals Multi-Targeted Molecular Docking, Pharmacokinetics, and Drug-Likeness Evaluation of Okra-Derived Ligand Abscisic Acid Targeting Signaling Proteins Involved in the Development of Diabetes

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5957
Author(s):  
Syed Amir Ashraf ◽  
Abd Elmoneim O. Elkhalifa ◽  
Khalid Mehmood ◽  
Mohd Adnan ◽  
Mushtaq Ahmad Khan ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Abscisic Acid ◽  
Molecular Docking ◽  
Binding Energy ◽  
Age Groups ◽  
Ppar Gamma ◽  
Inhibition Constant ◽  
Drug Candidate ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Diabetes mellitus is a global threat affecting millions of people of different age groups. In recent years, the development of naturally derived anti-diabetic agents has gained popularity. Okra is a common vegetable containing important bioactive components such as abscisic acid (ABA). ABA, a phytohormone, has been shown to elicit potent anti-diabetic effects in mouse models. Keeping its anti-diabetic potential in mind, in silico study was performed to explore its role in inhibiting proteins relevant to diabetes mellitus- 11β-hydroxysteroid dehydrogenase (11β-HSD1), aldose reductase, glucokinase, glutamine-fructose-6-phosphate amidotransferase (GFAT), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and Sirtuin family of NAD(+)-dependent protein deacetylases 6 (SIRT6). A comparative study of the ABA-protein docked complex with already known inhibitors of these proteins relevant to diabetes was compared to explore the inhibitory potential. Calculation of molecular binding energy (ΔG), inhibition constant (pKi), and prediction of pharmacokinetics and pharmacodynamics properties were performed. The molecular docking investigation of ABA with 11-HSD1, GFAT, PPAR-gamma, and SIRT6 revealed considerably low binding energy (ΔG from −8.1 to −7.3 Kcal/mol) and predicted inhibition constant (pKi from 6.01 to 5.21 µM). The ADMET study revealed that ABA is a promising drug candidate without any hazardous effect following all current drug-likeness guidelines such as Lipinski, Ghose, Veber, Egan, and Muegge.

Pharmacokinetics, Tissue Distribution, and Excretion Study of Cajanonic Acid A in Rats by UPLC-MS/MS

Planta Medica ◽  
2020 ◽  
Vol 86 (05) ◽  
pp. 312-318
Author(s):  
Li Zhang ◽  
Rui Chen ◽  
Yujuan Ban ◽  
Jin Cai ◽  
Jingang Peng ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Pigeon Pea ◽  
Negative Ion ◽  
Biological Behavior ◽  
Peroxisome Proliferator ◽  
Potential Candidate ◽  
Peroxisome Proliferator Activated Receptor ◽  
Single Reaction Monitoring ◽  
Negative Ion Mode

AbstractCajanonic acid A (CAA), a prenylated stilbene derivative extracted from the leaves of pigeon pea (Cajanus cajan), has been reported to possess inhibitory activity on the peroxisome proliferator-activated receptor gamma (PPARγ) and protein tyrosine phosphatase 1B (PTP1B). Its hypoglycemic activity in rats is comparable to that of the approved antidiabetic agent rosiglitazone. Therefore, CAA is a potential candidate for the treatment of type 2 diabetes and a lead compound for the discovery of novel hypoglycemic drugs. To achieve a thorough understanding of the biological behavior of CAA in vivo, our current study was designed to investigate the pharmacokinetics, bioavailability, distribution, and excretion of CAA in rats by UPLC-MS/MS. Chromatographic separation was performed on BEHC18 column (2.1 mm × 50 mm, 1.7 µm). Quantification was performed under the negative ion mode by using single reaction monitoring (SRM) of the transitions of m/z 353.14 → 309.11 for CAA and m/z 269.86 → 224.11 for genistein, respectively. Standard calibration curve showed excellent linearity (r2 > 0.99) within the range of 2 – 800 ng/mL. The accuracies and precisions were within the acceptance limits (all < 20%). CAA was quickly absorbed into bloodstream and distributed rapidly and widely to various tissues. The excretion ratio of CAA in the 3 main pathways via bile, feces, and urine was only 5.17%. These results indicate that CAA was quickly and thoroughly metabolized in vivo and excreted mainly as metabolites.

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