Ihab M. Al-Masri

Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine

Berberine was investigated as an inhibitor of human dipeptidyl peptidase IV (DPP IV) in an attempt to explain its anti-hyperglycemic activities. The investigation included simulated docking experiments to fit berberine within the binding pocket of DPP IV. Berberine was found to readily fit within the binding pocket of DPP IV in a low energy orientation characterized with optimal electrostatic attractive interactions bridging the isoquinolinium positively charged nitrogen atom (berberine) and the negatively charged acidic residue of glutamic acid-205 (GLU205) of DPP IV. Experimentally, berberine was found to inhibit human recombinant DPP IV in vitro with IC50 = 13.3 μM. Our findings suggest that DPP IV inhibition is, at least, one of the mechanisms that explain the anti-hyperglycemic activity of berberine. The fact that berberine was recently reported to potently inhibit the pro-diabetic target human protein tyrosine phosphatase 1B (h-PTP 1B) discloses a novel dual natural h-PTP 1B/DPP IV inhibitor.

Pharmacophore Modeling, Quantitative Structure–Activity Relationship Analysis, and in Silico Screening Reveal Potent Glycogen Synthase Kinase-3β Inhibitory Activities for Cimetidine, Hydroxychloroquine, and Gemifloxacin

The pharmacophoric space of glycogen synthase kinase-3beta (GSK-3beta) was explored using two diverse sets of inhibitors. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select optimal combination of pharmacophores and physicochemical descriptors that access self-consistent and predictive quantitative structure-activity relationship (QSAR) against 132 training compounds ( r (2) 123 = 0.663, F = 24.6, r (2) LOO = 0.592, r (2) PRESS against 29 external test inhibitors = 0.695). Two orthogonal pharmacophores emerged in the QSAR, suggesting the existence of at least two distinct binding modes accessible to ligands within GSK-3beta binding pocket. The validity of the QSAR equation and the associated pharmacophores was established by the identification of three nanomolar GSK-3beta inhibitors retrieved from our in-house-built structural database of established drugs, namely, hydroxychloroquine, cimetidine, and gemifloxacin. Docking studies supported the binding modes suggested by the pharmacophore/QSAR analysis. In addition to being excellent leads for subsequent optimization, the anti-GSK-3beta activities of these drugs should have significant clinical implications.

Inhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequent in vitro/in vivo evaluation

Curcumin was investigated as an inhibitor of glycogen synthase kinase-3β (GSK-3β) in an attempt to explain some of its interesting multiple pharmacological effects, such as its anti-diabetic, anti-inflammatory, anti-cancer, anti-malarial and anti-alzheimers properties. The investigation included simulated docking experiments to fit curcumin within the binding pocket of GSK-3β followed by experimental in vitro and in vivo validations. Curcumin was found to optimally fit within the binding pocket of GSK-3β via several attractive interactions with key amino acids. Experimentally, curcumin was found to potently inhibit GSK-3β (IC50 = 66.3 nM). Furthermore, our in vivo experiments illustrated that curcumin significantly increases liver glycogen in fasting Balb/c mice. Our findings strongly suggest that the diverse pharmacological activities of curcumin are at least partially mediated by inhibition of GSK-3β.

Discovery of DPP IV Inhibitors by Pharmacophore Modeling and QSAR Analysis followed by in silico Screening

Dipeptidyl peptidase IV (DPP IV) deactivates the natural hypoglycemic incretin hormones. Inhibition of this enzyme should restore glucose homeostasis in diabetic patients making it an attractive target for the development of new antidiabetic drugs. With this in mind, the pharmacophoric space of DPP IV was explored using a set of 358 known inhibitors. Thereafter, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and physicochemical descriptors that yield selfconsistent and predictive quantitative structure–activity relationships (QSAR) (r2287=0.74, F‐statistic=44.5, r2BS=0.74, r2 LOO=0.69, r2PRESS against 71 external testing inhibitors=0.51). Two orthogonal pharmacophores (of cross‐correlation r2=0.23) emerged in the QSAR equation suggesting the existence of at least two distinct binding modes accessible to ligands within the DPP IV binding pocket. Docking experiments supported the binding modes suggested by QSAR/pharmacophore analyses. The validity of the QSAR equation and the associated pharmacophore models were established by the identification of new low‐micromolar anti‐DPP IV leads retrieved by in silico screening. One of our interesting potent anti‐DPP IV hits is the fluoroquinolone gemifloxacin (IC50=1.12 μM). The fact that gemifloxacin was recently reported to potently inhibit the prodiabetic target glycogen synthase kinase 3β (GSK‐3β) suggests that gemifloxacin is an excellent lead for the development of novel dual antidiabetic inhibitors against DPP IV and GSK‐3β.

Pancreatic lipase inhibition activity of trilactone terpenes of Ginkgo biloba.

The prevalence of obesity is increasing at an alarming rate, but, unfortunately, only a few drugs are currently available on the market. In the present study, the methanolic extract of Ginkgo biloba L. (Ginkgoaceae) was investigated as an inhibitor of pancreatic lipase (PL) in an attempt to explain its hypolipidaemic activity. In vitro assay of G. biloba leaves extract revealed a substantial PL inhibition activity (IC50 = 16.5 µg/mL). Further investigation was performed by employing theoretical docking simulations and experimental testing to uncover the active constituents responsible for G. biloba anti-lipase activity. Virtually, terpene trilactones, including ginkgolides and bilobalide, were found to fit within the binding pocket of PL via several attractive interactions with key amino acids. Experimentally, ginkgolides A, B, and bilobalide were found to inhibit PL significantly (IC50 = 22.9, 90.0, and 60.1 µg/mL, respectively). Our findings demonstrated that the hypolipidaemic effects of G. biloba extract can be attributed to the inhibition of PL by, at least in part, terpene trilactones. In conclusion, this work can be considered a new step towards the discovery of new natural safe hypolipidaemic PL inhibitors.

Olanzapine inhibits glycogen synthase kinase-3β: An investigation by docking simulation and experimental validation

Olanzapine was investigated as an inhibitor of glycogen synthase kinase-3beta (GSK-3beta) in an attempt to evaluate its effect on blood glucose level. The investigation included simulated docking experiments to fit olanzapine within the binding pocket of GSK-3beta followed by in vitro enzyme inhibition assay as well as in vivo subchronic animal treatment. Olanzapine was found to readily fit within the binding pocket of GSK-3beta in a low energy orientation characterized with optimal attractive interactions bridging the tricyclic thienobenzodiazepine nitrogen and sulfur atoms of olanzapine and the residue of VAL-135 of GSK-3beta. In vivo experiments showed a significant decrease in fasting blood glucose level in Balb/c mice at 1.0, 2.0 and 3.0 mg/kg dose levels (P<0.05) and 6 fold increase in liver glycogen level at the 3 mg/kg dose level (P<0.001). Moreover; olanzapine was found to potently inhibit recombinant GSK-3beta in vitro (IC(50) value=91.0 nM). Our findings strongly suggest that olanzapine has significant GSK-3beta inhibition activity that could justify some of its pharmacological effects and glucose metabolic disturbances.

Antioxidant, antihyperuricemic and xanthine oxidase inhibitory activities of Hyoscyamus reticulatus.

Context: Xanthine oxidase (XO) is a key enzyme in the pathophysiological homeostasis of hyperuricemia. It catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid, the reaction involves the formation of free radical intermediates and superoxide byproducts. Objectives: This study was undertaken to investigate the antioxidant, antihyperuricemic, and xanthine oxidase inhibitory potentials of Hyoscyamus reticulatus L. (Solanaceae) extract. Materials and methods: The antioxidant potency was measured using the ABTS•+ scavenging capacity system, which includes Trolox as a standard. The xanthine oxidase inhibitory activity of the extract was quantitated in vitro by measuring the decline in the catalytic rate of xanthine oxidase following incubations with the plant extracts and using xanthine as a substrate. The hypouricemic potential of the extract was evaluated using an in vivo model for hyperuricemia. We tested three different doses of the extract and allopurinol was used as standard antihyperuricemic positive control. Results: H. reticulatus aqueous extract exhibited significant antioxidant scavenging properties (533.26 μmol TE/g dry extract weight) and inhibitory effect on xanthine oxidase activity (IC50 12.8 μg/mL). Furthermore, oral administration of the aqueous extract significantly reduced serum urate levels in oxonate-induced hyperuricemic mice in a dose-dependent manner. Discussion and conclusion: Our results suggest that the aqueous extract of H. reticulatus aerial parts might have great potential as an antioxidant and a hypouricemic agent. Our lab is currently identifying the active compounds in the extract to which the biological activities could be attributed.

New leads for DPP IV inhibition: structure-based pharmacophore mapping and virtual screening study

Dipeptidyl peptidase IV (DPP IV) is an attractive target for the development of new antidiabetic drugs. DPP IV inhibitors improve glycemic control by preventing the rapid inactivation of the incretin hormones; glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide. In the current study, virtual screening, using 2D and 3D filters implemented in a hierarchical cascade, was employed to identify new DPP IV inhibitors. Co-crystallized ligands, with potent DPP IV-inhibitory activities, were utilized to generate structure-based pharmacophore models using DS Visualizer software. The derived pharmacophore maps were validated using in-house built database containing active and inactive DPP IV inhibitors. Subsequently, the optimum validated pharmacophore model was used as a search query against two 3D-databases (NCI and in-house built drug databases). Further hit filtration was carried out employing 2D virtual filters based on Lipinski’s rule of 5; number of rotatable bonds and other physicochemical filters. 3D filter using high-throughput molecular docking was also applied. As a result, 5 novel DPP IV inhibitors were discovered as potential lead compounds and later confirmed via in vitro bioassay.

Pancreatic Lipase Inhibition by Papaverine: Investigation by Simulated Molecular Docking and Subsequent In Vitro Evaluation

In order to develop safe and effective lipid lowering drug that affecting the absorption of dietary lipids, the pancreatic lipase inhibitory effect of papaverine alkaloid was probed. The investigation included molecular docking to fit papaverine into the binding site of pancreatic lipase employing optimal set of parameters succeeded in retrieving the closest model to the cocrystallized pose. Docking simulation suggested four binding modes for papaverine. The highest ranking binding mode have potential hydrophobic interactions with the key amino acids Phe-215, Ala-178, Pro-180 and Ala-259 and potential aromatic stacking between isoquinoline ring and Phe-77 and Tyr-114. Moreover, papaverine forms strong hydrogen bonds with the key amino acid Ser-152 in the catalytic triad. Experimentally, papaverine illustrated substantial in vitro inhibitory effect against PL with IC50 = 36.2 µg/ml (106.6 μM).

Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones

Fluoroquinolones (FQs) have been identified recently as potent inhibitors of pancreatic lipase (PL). The aim of this study was to synthesize novel FQs and triazolofluoroquinolones (TFQs) and to evaluate them in vitro with respect to their antilipolytic efficacy and potency properties. The PL‐IC50 values of 12 FQs and TFQs (3 (a–c)–6 (a–c)) were in the range of 12.5–189.1 μm. These values are further supported by docking studies. The suggested association between obesity and colorectal cancer initiated the evaluation of antiproliferative activity of the new FQs and TFQs against a panel of obesity‐related colorectal cells (HT29, HCT116, SW620 CACO2, and SW480). Sulforodamine B colorimetric assay revealed that some derivatives exhibited unselective cytotoxicity against HT29, HCT116, SW620 CACO2, and SW480. Remarkably, FQ 4as selective cytotoxicity against HCT116 was found valuable with IC50 value of 4.2 μm which exceeds that of cisplatin with a substantial selective cytotoxicity in periodontal ligament fibroblasts. In conclusion, FQ and TFQ derivatives may unveil new antiobesity and anticancer agents in the future.