Combinatorial Chemistry & High Throughput Screening - Volume 19, Issue 9, 2016

Aim and Objective: Anaplastic lymphoma kinase, an insulin receptor protein-tyrosine kinase, is a very attractive receptor protein target for anticancer therapy. This study was undertaken to identify novel structurally diverse anaplastic lymphoma kinase inhibitors. Material and Method: Pharmacophore hypotheses modeling, virtual screening and molecular docking were used to detect potential inhibitors of anaplastic lymphoma kinase in this paper. Results: After the generation of ten pharmacophore hypotheses, Hypo1 with the highest correlation value (0.981), lowest RMS (0.565), highest cost difference (83.850) along with four typical chemical features was regarded as the best hypothesis. Hypo1 contains a hydrogen bond acceptor, a hydrogen bong donor, a hydrophobic and a ring aromatic feature. And then, hypo1 was validated and used to screen three databases after screened by Lipinski’s rule of five. 3015 hits screened by Hypo1 were submitted to molecular docking based on the crystal structure of anaplastic lymphoma kinase. Conclusion: all the seven molecules formed hydrogen bond interaction with Met1199 as well as formed several other hydrogen bond interactions with different residues. All of them formed Van Der Waals interaction with hydrophobic pocket which made up of residues of Ala1148, Leu1256, Leu1196, Leu1198 Val1130 and Val1180. Some of them also formed van der Waals interaction in somewhere else of protein pocket.

Aim and objective: Overexpression of efflux pumps belonging to the Resistance Nodulation cell Division (RND) family is the most important intrinsic resistance mechanism of Pseudomonas aeruginosa. Hence, it is imperative to identify suitable efflux pump inhibitors (EPI) that can lead to increased intracellular concentration of antibiotics by blocking the pump. This study was undertaken to identify a putative plant based efflux pump inhibitor for RND efflux pump of P. aeruginosa. Material and method: Using molecular docking approach, 328 secondary plant metabolites have been screened for their inhibitory activity against cytoplasmic exporter protein MexB of MexAB-OprM efflux pump of P. aeruginosa. After the initial in silico screening, the shortlisted compounds were subjected to in vitro test for efflux pump inhibitory activity using double disc synergy test. A combinatorial library of 1000 molecules was generated from active p-coumaric acid and docked with MexB protein to find a suitable EPI with better binding efficacy compared to the p-coumaric acid. Results: Preliminary screening resulted in five plant-based natural products with significant docking score and were subsequently subjected to double disc synergy test. p-Coumaric acid , amongst the five, was found to potentiate activity of ciprofloxacin in MexAB-OprM overexpressing P. aeruginosa strain. Library compound 482, i.e 4-(4-((Z)-2-carboxy-2-((Z)-2,3-dihydrobenzo[e][1,4]diazepin-1-yl)-1-(4- hydroxyphenyl)vinylamino) phenylsulfonamido)-2-hydroxybenzoic acid, a derivative of p-coumaric acid exhibited the highest docking score of -42.1030 Kcal/mol, which was much higher than parent compound (-17.9403 Kcal/mol) and also known EPI, MC-207,110 (-28.0960 Kcal/mol). Conclusion: p-Coumaric acid and its derivative, 4-(4-((Z)-2-carboxy-2-((Z)-2,3-dihydrobenzo[e][1,4] diazepin-1-yl)-1-(4-hydroxyphenyl)vinylamino)phenylsulfonamido)-2-hydroxybenzoic acid may be used as potential lead molecules for effective RND efflux pump inhibition in P. aeruginosa.

Background: The breast is an important biological system of human with two distinct states, i.e. normal and tumoral. Research on breast cancer could be based on systematic modeling to contrast the system structures of these two states. Objective: We use mutual information for the construction of the gene network of breast tissues and normal tissues. These gene networks are analyzed, compared as well as classified. We also identify structural key genes that may play significant roles in the formation of breast cancer. Method: Gene networks are constructed using with mutual information values. Four structural parameters, namely node degree, clustering coefficient, shortest path length and standard betweenness centrality, are used for analyzing the gene networks. Support vector machine is used to classify the gene networks into normal and disease states. Genes with standard betweenness centrality of greater than 0.3 are identified as possibly significant in the development of breast cancer. Result: The classification of the gene networks into normal and disease states suggest that the vectors of parameters are linearly separable by any combinations of these four structural parameters. In addition, the six genes BAK1, RRAD, LCN2, EGFR, ZAP70 and FOSB are identified to possibly play significant roles in the formation of breast cancer. Conclusion: In this work, four structural parameters have been generalized to the relevance networks. These parameters are found to distinguish gene networks of normal and cancerous breast tissues at different thresholds. In addition, the six genes identified may motivate further studies and research in breast cancer.

A convenient procedure for the preparation of 1-(1-Propylsulfonic)-3- methylimidazolium thiocyanate as a novel Brønsted acidic ionic liquid thiocyanation agent and highly efficient heterogeneous catalytic is described. This catalyst is used in regioselective thiocyanation of indoles, anilines, pyrroles and their derivatives (aromatic and heteroaromatic organic compounds) in the presence of H2O2 as a mild and oxidant in EtOH:H2O (1:1 v/v). These reactions are performed under mild and simple conditions and give regioselective products in high yields and short reaction time.

Aim and objective: Since a wide range of biological and pharmaceutical activities of barbituric acid, 4-hydroxycoumarin and their derivatives have been disclosed until now, in the domain of our interest to find newly catalytic routes for highly efficient synthesis of potentially interesting biologically active organic compounds, and extension of their areas, herein we introduce a three component combinatorial reaction based on (N,N-dimethyl)barbituric acid and 4- hydroxycoumarin scaffolds. Material and method: All starting materials were purchased from Merck chemical company and were applied without further purifications. Catalytic reaction between barbituric acid (or N,N-dimethyl barbituric acid), 4-hydroxycoumarin, and a wide range of aryl aldehydes by employing titanium dioxide nanowires (TiO2 NWs) is successfully performed under solvent-free conditions at 100 °C, and led efficiently to obtain target products. Results: From loading above mentioned three component reaction, starting materials in the presence of catalytic amounts of TiO2 NWs as a key factor were condensed together via three C-C bond formation to obtain 12 newly prepared compounds. This procedure profits some advantages such as an efficiency, environmental safety and high recyclability of nano-catalyst. Conclusion: In this work, by the use of a green adapted method in a condensation three component reaction catalyzed by TiO2 NWs as an efficient nano-catalyst, some newly prepared products were prepared in a one pot, and the scope of potentially interesting biologically active organic compounds which can be duly considered by biologists and pharmacologists was developed.

Background: Histone deacetylase (HDAC) inhibitors can reactivate gene expression and inhibit the growth and survival of cancer cells. Objective: To identify the important pharmacophoric features and correlate 3Dchemical structure with biological activity using 3D-QSAR and Pharmacophore modeling studies. Method: The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. Pharmacophore hypothesis represents the 3D arrangement of molecular features necessary for activity. A series of 55 compounds with wellassigned HDAC inhibitory activity were used for 3D-QSAR model development. Results: Best 3D-QSAR model, which is a five partial least square (PLS) factor model with good statistics and predictive ability, acquired Q2 (0.7293), R2 (0.9811), cross-validated coefficient rcv 2=0.9807 and R2 pred=0.7147 with low standard deviation (0.0952). Additionally, the selected pharmacophore model DDRRR.419 was used as a 3D query for virtual screening against the ZINC database. In the virtual screening workflow, docking studies (HTVS, SP and XP) were carried out by selecting multiple receptors (PDB ID: 1T69, 1T64, 4LXZ, 4LY1, 3MAX, 2VQQ, 3C10, 1W22). Finally, six compounds were obtained based on high scoring function (dock score -11.2278-10.2222 kcal/mol) and diverse structures. Conclusion: The structure activity correlation was established using virtual screening, docking, energetic based pharmacophore modelling, pharmacophore, atom based 3D QSAR models and their validation. The outcomes of these studies could be further employed for the design of novel HDAC inhibitors for anticancer activity.

Background: Camptothecin is a quinoline alkaloid, isolated from the Chinese tree Camptotheca acuminate which exhibits its cytotoxic activity by the inhibition of nuclear enzyme Topoisomerase I (topo I). Camptothecin and its analogues forms a covalent bond with DNA which can arrest the tumor growth by slowing the religation step of the enzyme and stabilize the covalent adduct between topo I and DNA. Besides its strong anticancer potential, the limited solubility as well as instability of the hydroxylactone ring (Ring E) limits the clinical application of Camptothecin. This study was undertaken to identify novel compounds having anticancer activity with mechanism of action similar to that of Camptothecin using scaffold perception technique. Materials and methods: We developed a common pharmacophore hypothesis using 32 camptothecin analogues, which was used for preliminary screening of large databases (ZINC “drug-like” database) to make sure, to include only compounds containing the key structural features needed to be Topoisomerase I inhibitors. In terms of a structure based approach, we systematically investigated various types of docking protocols to identify the most active compounds from the identified hit molecules. A post docking energy calculation was also carried out by MM/GBSA method. Results: From the selected series of camptothecin analogs, a 3D-QSAR pharmacophore model was developed. The model consists of one acceptor site, one donor site, one hydrophobic site and two aromatic functions (ADHRR). Then, the pharmacophore model was employed as 3D search query to screen compounds from ZINC database which followed by molecular docking study and MM/GBSA calculation identified 2 lead molecules which, however, were not biologically validated. In silico studies reveals that the identified lead molecules have a better binding affinity than the co crystallized ligand. Conclusion: The identified molecules were able to bind to the active site of Topo-I enzyme similar to that of Camptothecin and the ADME properties were within the acceptable range defined for human use. The new molecules identified by virtual screening as such or on further optimization can be used as potential leads in designing Topoisomerase I inhibitors.

Background: Fenobam is a non-competitive mGluR5 antagonist as an anxiolytic agent. Objective: In this research a new series of fenobam analogues containing thiazole moiety instead of imidazole ring were designed and synthesized. Methods: The ureido-substituted products were synthesized from reaction of amino thiazole derivatives and isocyanate derivatives in dichloromethane solvent under microwave and ultrasonic irradiation condition. The synthesized compounds structures were established by means of IR, 1HNMR, 13CNMR spectroscopic data. Then, docking calculations were performed on the active site of mGLuR5 and compared to Fenobam as a reference drug by using AutoDock program. The molecular dynamics (MD) simulations were done using GROMACS 5.0.5. Results: Docking studies suggested that all of the compounds possess better binding energy when compared to fenobam. The results of MD simulations might offer the binding mode of ligand (3b), accuracy of docking and the reliability of active conformations which obtained by AutoDock. Conclusion: New derivatives of fenobam were designed and synthesized that have the better insilico results compared to fenobam and will evaluate in future studies.

Aim and Objective: C-Jun-N-terminal kinase -1 (JNK -1) is a seriene/threonine kinase protein and a member of mitogen activated protein family (MAP– Kinase). The activation of JNK-1 leads to cell proliferation, cell death, DNA repair and metabolism. In our study we aim in creating a novel JNK-1 inhibitor. Material and Method: Various computational techniques like 3D-atom based QSAR analysis; pharmacophore based virtual screening; molecular docking and Density functional theory approaches are utilised to obtain novel JNK-1 inhibitor. Result: Pharmacophores with pharmacophoric features as two hydrogen bond acceptors (A), one hydrogen bond donor (D), one hydrophobic (H) and one aromatic ring (R) are generated. Amongst the generated pharmacophore hypothesis, AADHR.6 was found to have good survival score of 3.214 and is used to derive atom based 3D – QSAR model. The obtained 3D – QSAR model has excellent squared correlation coefficient value (R2= 0.9272) and a good fisher ratio (F= 273.9). The reliability and robustness of the chosen model is validated both internally and externally to obtain good statistical results. The model AADHR.6 is used in virtual screening of Zinc and NCI databases for potential inhibitors. Resulting hit compounds from virtual screening are then subjected to docking and Density Functional Theory (DFT) studies. Conclusion: Both docking and DFT studies brings out two lead compounds with good inhibitory activity against the receptor. Thus the work presents a novel JNK – 1 inhibitor that can serve as potential therapeutics for the treatment of various diseases associated with abnormal JNK -1 functioning.