Mutasem O. Taha

Synthesis of Chitosan Succinate and Chitosan Phthalate and Their Evaluation as Suggested Matrices in Orally Administered, Colon‐Specific Drug Delivery Systems

The naturally occurring polymer chitosan was reacted separately with succinic and phthalic anhydrides. The resulting semisynthetic polymers were assessed as potential matrices for colon‐specific, orally administered drug delivery. Sodium diclofenac was used as the dispersed model drug. The prepared matrices were incorporated into tablets, which were evaluated in vitro. The evaluation included dissolution studies conducted under simulated gastrointestinal conditions of pH and transit times. The percentage fluid uptake was used to indicate the ability of the matrix to protect an embedded drug from gastric juices. The prepared matrices resisted dissolution under acidic conditions. On the other hand, improved drug release profiles were observed under basic conditions. Therefore, the results suggest the suitability of the prepared matrices in colon specific, orally administered drug delivery system. However, future in vivo testing is planned to fully establish the suitability of the prepared polymers for colon‐specific drug delivery.

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.

Synthesis of iron-crosslinked chitosan succinate and iron-crosslinked hydroxamated chitosan succinate and their in vitro evaluation as potential matrix materials for oral theophylline sustained-release beads

Chitosan succinate (CS) and hydroxamated chitosan succinate (HCS) were prepared. The generated semisynthetic polymers were employed in the formation of drug-loaded, iron(III)-crosslinked polymeric beads. Infrared spectroscopy was employed to prove the crosslinking. The produced beads were evaluated in vitro as drug prolonging and potentially orally administered delivery system. Theophylline was used as the loaded model drug. The generated beads proved to be successful in prolonging drug release. Iron leaching from the generated beads was minimal (<2%), and it only took place under acidic conditions (pH 1).

Combining ligand-based pharmacophore modeling, quantitative structure-activity relationship analysis and in silico screening for the discovery of new potent hormone sensitive lipase inhibitors.

Hormone sensitive lipase (HSL) has been recently implicated in diabetes and obesity, prompting attempts to discover new HSL inhibitors. Toward this end, we explored the pharmacophoric space of HSL inhibitors using four diverse sets of compounds. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of yielding a self-consistent and predictive quantitative structure-activity relationship (QSAR) (r = 0.822, n = 99, F = 11.1, r LOO (2) = 0.521, r PRESS (2) against 23 external test inhibitors = 0.522). Interestingly, two pharmacophoric models emerged in the QSAR equation suggesting at least two binding modes. These pharmacophores were employed to screen the National Cancer Institute (NCI) list of compounds and our in-house built database of established drugs and agrochemicals. Active hits included the safe herbicidal agent bifenox (IC 50 = 0.43 microM) and the nonsteroidal anti-inflammatory naproxen (IC 50 = 1.20 microM). Our active hits undermined the traditional believe that HSL inhibitors should possess covalent bond-forming groups.

Elaborate ligand-based pharmacophore exploration and QSAR analysis guide the synthesis of novel pyridinium-based potent β-secretase inhibitory leads

Beta-secretase (BACE) inhibitors have potential as anti-Alzheimers disease treatments prompting us to explore the pharmacophoric space of 129 known BACE inhibitors. QSAR analysis was employed to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of explaining bioactivity variation (r(2)=0.88, F=60.48, r(LOO)(2)=0.85, r(PRESS)(2) against 25 external test inhibitors=0.71). We were obliged to use ligand efficiency as the response variable because the logarithmic transformation of bioactivities failed to access self-consistent QSAR models. Three pharmacophoric models emerged in the successful QSAR equation suggesting at least three binding modes accessible to ligands within BACE binding pocket. QSAR equation and pharmacophoric models were validated through ROC curves and were employed to guide synthesis of novel pyridinium-based BACE inhibitors. The best inhibitor illustrated an IC(50) value of 1.0 microM against BACE.

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.

Pharmacophore Modeling, Quantitative Structure−Activity Relationship Analysis, and Shape-Complemented in Silico Screening Allow Access to Novel Influenza Neuraminidase Inhibitors

Neuraminidase (NA) enzyme is one of the valid targets against influenza viruses. With this in mind, the pharmacophoric space of influenza NA was explored using three sets of diverse inhibitors. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select optimal combinations of pharmacophoric models and 2D descriptors capable of yielding self-consistent and predictive quantitative structure-activity relationships (QSARs) against 181 training compounds. The optimal QSAR equations were validated against 43 external test compounds with r(2)(PRESS) values ranging from 0.488 to 0.591. Interestingly, five orthogonal pharmacophores emerged in the optimal QSAR equations suggesting the existence of several distinct ligand/NA binding modes within the NA binding pocket. The resulting pharmacophores were complemented with tight shape constraints and employed as three-dimensional (3D) search queries against the National Cancer Institute (NCI) list of compounds. Several hits exhibited potent inhibitory activities against NA. The highest ranking hit demonstrated an in vitro IC(50) value of 1.8 muM. Docking studies supported the binding modes suggested by our pharmacophore/QSAR analysis.

Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration

Cholesteryl ester transfer protein (CETP) is involved in trafficking lipoprotein particles and neutral lipids between HDL and LDL and therefore is considered a valid target for treating dyslipidemic conditions and complications. Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explore the structural requirements for potent CETP inhibitors. Two pharmacophores emerged in the optimal QSAR equation (r(2)=0.800, n=96, F=72.1, r(2)(LOO) =0.775, r(2)(PRESS) against 22 external test inhibitors=0.707) suggesting the existence of at least two distinct binding modes accessible to ligands within CETP binding pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic (ROC) curve profiles. The validity of our modeling approach was experimentally established by the identification of several CETP inhibitory leads retrieved via in silico screening of the National Cancer Institute (NCI) list of compounds and an in house built database of drugs and agrochemicals. Two hits illustrated low micromolar IC(50) values: NSC 40331 (IC(50)=6.5 microM) and NSC 89508 (IC(50)=1.9 microM). Active hits were then used to guide synthetic exploration of a new series of CETP inhibitors.

Elaborate Ligand-Based Modeling Reveals New Nanomolar Heat Shock Protein 90α Inhibitors

Heat shock protein (Hsp90α) has been recently implicated in cancer prompting several attempts to discover and optimize new Hsp90α inhibitors. Toward this end, we explored the pharmacophoric space of 83 Hsp90α inhibitors using six diverse sets of inhibitors to identify high-quality pharmacophores. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing a self-consistent quantitative structure activity relationship (QSAR) of optimal predictive potential (r(67)(2)=0.811, F 42.8, r(LOO)(2)=0.748, r(PRESS)(2) (against 16 external test inhibitors) = 0.619). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within the Hsp90α binding pocket. Receiver operating characteristic (ROC) curves analysis established the validity of QSAR-selected pharmacophores. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds and our in-house-built drugs and agrochemicals database (DAC). Twenty-five nanomolar and low micromolar Hsp90α inhibitors were identified. The most potent were formoterol, amodaquine, primaquine, and midodrine with IC(50) values of 3, 5, 6, and 20 nM, respectively.