Letters in Drug Design & Discovery - Volume 8, Issue 3, 2011

The article describes the pharmacological examinations of clathrates of warfarin (WF) with glycyrrhizic acid (GA) and arabinogalactan (AG). A direct connection between the clathrate structure and the pharmacons anticoagulative properties was observed. A 20 mg/kg (WF 2 mg/kg) dose of WF: GA 1:10 clathrate causes the increase in prothrombin time (PT) only in 54 hours, after 3 administrations. In contrast, a 20 mg/kg (WF 2 mg/kg) dose of WF: AG 1:10 clathrate leads to an increase in PT in 24 and 48 hours after a single administration, which corresponds to the effect of a comparator agent WF (2 mg/kg).

Receptor tyrosine kinases (RTKs) are crucial targets in the pathway of angiogenesis and the currently used antiangiogenic drugs have limited efficiency with associated toxicity. In our continuous search for new and potent multitarget anti-angiogenic lead compounds, we have conducted in-silico interaction and inhibition studies of the selected aglycones of steroidal glycoalkaloids (GAs) and selected anti-angiogenic drugs, against the EGFR, VEGFR-1, VEGFR-2 using the AutoDock Tools 4.0 and other online bioinformatics softwares. The docking results have been interpreted in terms of binding energies (kcal/mol) and inhibition constant (μM). In our study, aglycones [solanidine (solanid-5-en-3β-ol), solasodine (Solasod-5-en-3β-ol) and tomatidine (5α-Tomatidan-3β-ol)] gave promising and comparable results with the antiangiogenic drugs (Gefitinib, Lapatinib, Axitinib and Motasenib). All the test aglycones expressed significant inhibition against RTKs under study, but tomatidine emerged as a most potent multi-target inhibitor of RTKs. The inhibition constant of tomatidine was observed almost 2-folds less compared to Gefitinib targeting against EGFR and 5-folds less to Axitinib, the standard drug against VEGFR-2. Moreover, these aglycones fulfilled the drug likeliness properties, when analyzed by Lipinskis Rule of Five. In addition to this, the in-silico toxicity studies of aglycones remarkably showed no mutagenecity and tumorigenecity compared to the standard drugs. Our results for the first time report that these novel aglycones of GAs may be significant lead compounds in the development of new and effective multi-target antiangiogenic drugs with the least or no toxicity. In addition, the wet lab experiments are underway to support these in-silico results.

Our previous kinetics studies demonstrate that the natural product galangin exhibits a high-affinity inhibition of 153 nM towards human cytochrome P450 1A2. However, much less is known about the inhibitory mechanism of galangin against 1A2. To better understand the inhibitory mechanism of galangin towards 1A2, a modeling study including molecular docking and molecular dynamics simulations was performed. The binding pattern after molecular dynamics simulations reveals that galangin represents a similar binding pattern as another strong inhibitor α-naphthoflavone with a few exceptions. The O7 atom of galangin forms an H-bond with the O atom of Asn312. An intramolecular H-bond is observed between the O5 and O4 atoms of galangin. Energetic analysis indicates that galangin exhibits a less negative predicted binding free energy of -22.61 kcal/mol than α-naphthoflavone (-23.54 kcal/mol), which is consistent with inhibitory experiment (153 nM and 49 nM). Additionally, our results suggest that the inhibitory mechanism of galangin is mainly dominated by electrostatic/H-bond and hydrophobic/van der Waals interactions. The present work also revealed that the additional 4' hydroxyl group at the B ring would weaken the intermolecular interactions between kaempferol and 1A2, which was validated by our kinetics experiment (IC50 = 1 490 nM).

Designing kinase inhibitors is always an area of interest because kinases are involved in many diseases. In the last one decade a large number of kinase inhibitors have been launched successfully; six inhibitors have been approved by FDA and more are under clinical trials. Cross-reactivity or off-target is one of the major problems in designing inhibitors against protein kinases; as human, have more than 500 kinases with high sequence similarity. In this study an attempt has been made to develop a model for predicting specificity and cross-reactivity of kinase inhibitors. The dataset used for testing and training consists of binding affinities of 20 chemical kinase inhibitors with protein kinases. We developed QSAR based SVM models for predicting binding affinity of an inhibitor against protein kinases using most relevant 5,10 and 15 structure descriptors and achieving average correlation of 0.64, 0.488 and 0.442 respectively. In order to predict specificity and cross-reactivity of an inhibitor, we developed 16 QSAR based SVM models for 16 protein kinases; one model for each kinase. We achieved average correlation 0.719 between actual and predicted binding affinity using kinase specific models. Based on the above study a web server DMKPred has been developed for predicting binding affinity of a drug molecule with 16 kinases. The SVM based model used in this study can be used to predict kinase specific inhibitors. This study will be useful for designing kinase specific inhibitors.

The pyrrolopyrimidine derivatives have been regarded as a novel class of LIM-kinase 2 inhibitor. To explore the relationship between the structures of substituted pyrrolopyrimidine derivatives and their inhibitory activities against LIMK2, CoMFA and CoMSIA analyses, and molecular docking studies were performed on a dataset of forty-one compounds. The two 3D-QSAR models resulted from thirty-one molecules in the training set gave r2 cv values of 0.635 and 0.660, r2 values of 0.973 and 0.965, respectively. The predictive ability of CoMFA and CoMSIA, determined using a test set of ten compounds, gave predictive correlation coefficients of 0.971 and 0.964, respectively. 3D contour maps generated from CoMFA and CoMSIA along with the docking binding structures provided enough information about the structural requirements for better activity. The results can serve as a useful guideline to design novel LIMK2 inhibitors with better potencies.

We report the initial results of our study into a series of thiosemicarbazone-based compounds as potential inhibitors of estrone sulfatase (ES). The results show the compounds to be weak inhibitors of ES in comparison to the standard estrone-3-O-sulfamate used within the study and which possessed 98 inhibition under similar conditions.

Schizophrenia is a disorder of abnormal neurodevelopment, with minor physical anomalies, neurological soft signs, and abnormalities of brain structure and functions. It is estimated that one percent of the worlds population is suffering from this disease. Extensive data recommend that genetic abnormalities of dopamine function are well-known features of schizophrenia that may play a unique role for catechol-O-methyl transferase (COMT) in dopamine-mediated prefrontal information processing in working memory. In this work, we describe a structure- based design approach that uses three-dimensional modeling of COMT. The modeled COMT structure was docked with twenty two inhibitors. The calculated binding energies from the docking analysis were also performed. The 7,8-dihydroxyflavone ligand was fitted to this site on membrane-bound COMT (MB-COMT) and soluble COMT (S-COMT) judging by docking studies, forming hydrogen bonds principally with the Lys144 residues. We have identified the toxicity using zebrafish model with the molecule (7,8-dihydroxyflavone). During the toxicity assay, no abnormality was found in embryonic development of zebrafish. So, it indicates that 7,8-dihydroxyflavone has no toxic effect on zebrafish larvae. So, we are very hopeful that this molecule may be a good drug candidate for future; however, more studies are required in this relation.

In an effort to aid the design of dual-inhibitors of types 1 and 3 of the 17β-hydroxysteroid dehydrogenase (17β-HSD), we report the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of trifluoromethanesulfonate derivatives of 4-hydroxyphenyl ketone-based compounds which were found to be weak inhibitors of types 1 and 3.

In the present study, the ameliorative effect of a bischalcone (2E,5E)-2,5-bis(3-methoxy-4-hydroxy- benzylidene) cyclopentanone (CA), a curcumin analog was studied on Drosophila melanogaster (oregon K strain) in vivo by inducing oxidative stress using paraquat. Curcumin (CU) was taken as standard for studies. In negative geotaxis assay it was found that CA was able to rescue the flies significantly from deteriorating locomotor dysfunctions. A docking study for antialzeimers activity of CA was carried out by targeting the proteins Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE). It binds effectively to the target proteins.

A novel class of compounds with structure Aryl propyl acridone-4-carboxamides were synthesized by conventional and microwave (MW) irradiation methods and evaluated for their inhibitory effects on the transport activity of P- glycoprotein (P-gp) by standard Hoechst 33342 assay method. The title compounds with phenoxy substitution exhibited better activity.

Different imidazole derivatives were prepared by utilizing the intermediate 2-(2,4,5-triphenyl-1H-imidazol-1- yl)acetohydrazide (3) using microwave irradiation method besides the traditional ones. They were used for synthesis of some new derivatives of 2,5-disubstituted-1,3,4-oxadiazole, pyrazole, 2,5-dimethylpyrrole and nitrogen containing five membered rings. All the synthesized compounds were characterized by IR, 1H & 13C NMR and mass spectral data. The antibacterial, antifungal (MIC) and antioxidant activities were verified for all the synthesized compounds.

Gallic acid (3,4,5-trihydroxybenzoic acid) a plant phenolic antioxidant is known for its strong antiinflammatory, anti-mutagenic and anti-carcinogenic activities. But due to a lower half-life and rapid clearance by the body, frequent administration of the molecule is required. To improve the bioavailability and prolong its duration in the body system, its phospholipid complex was prepared and evaluated for various physico-chemical parameters like encapsulation efficiency, scanning electron microscopy, differential scanning calorimetry, X-ray powder diffractometry, IR spectroscopy and dissolution study. The phospholipid complex of gallic acid (Ga-Pc) was found to be fluffy and porous with rough surface morphology. FTIR, DSC and XRPD data confirmed the complex formation. The 89.1 of gallic acid was encapsulated in the phospholipid complex. A controlled release pattern was shown by the complex (which showed continuous release up to 93 of gallic acid) at the end of 24 h in comparison to free gallic acid (which showed 81.91 burst release just in the 0.5 h).

As per Bentham Science’s policy, the following article has been retracted at the request of the Editor-in-Chief and Authors of the journal Letters in Drug Design & Discovery (LDDD). Title “Solubilization and Amorphization of Non Steroidal Anti-Inflammatory Drug with Low Molecular Weight Chitosan for a New Guar-Based Colon Delivery Formulation; Letters in Drug Design & Discovery, vol. 8(3); pp. 292-301.” Authors Kadria A. Elkhodairy, Nahla S. Barakat and Fars K. Alanazi The above article is a plagiarized version of another article entitled “Low molecular weight chitosan as a vehicle for solubilization and amorphization of nonsteroid anti-inflammatory drug for a new guar gum based column drug delivery formulation” International Journal of Current Research and Review, August 2010, Vol. 2, No. 8, Pp. 62-69 written by the same authors and published in Letters in Drug Design & Discovery, March 2011, Vol. 8, No. 3, Pp 292-301. Bentham Science apologizes to the readers of the journal for not detecting this omission during the publishing process. We thank Professor Kadria A. Elkhodairy for bringing this breach of conduct to our attention. BENTHAM SCIENCE DISCLAIMER It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.