Letters in Drug Design & Discovery - Volume 14, Issue 10, 2017

Objective: 3D-QSAR study was carried out by using Topomer comparative molecular field analysis method. It was applied for three peptides which are bitter tasting threshold of dipeptide, oxytocin and bradykinin-potentiating peptides. Methods: The structures of all peptide drugs were built by using the Build Protein function and all molecular modeling calculations were performed in the SYBYL2.0. Each peptide was fragmented into different sets of groups. Steric and electrostatic interaction energies were calculated by the carbon sp3 probe. PLS regression was used to obtain QSAR model. Results: In the QSAR model for bitter tasting threshold of di-peptide, cross-validated coefficient (Q2) was 0.614, squared correlation coefficient between predicted and observed activities (R2) was 0.708 and external multiple correlation coefficient (Qext 2) was 0.828. The corresponding data onto the oxytocin were 0.835, 0.899, 0.795 and for bradykinin-potentiating peptides were 0.624, 0.870. 0.670. Conclusion: The present work was employed Topomer CoMFA to perform for three peptide drugs,and the calculated statistical parameters (high Q2, R2, Qext 2, F and SEE values) indicate 3DQSAR models have a high predictability for peptide drugs. It can contribute to the design of novel bioactive peptides.

Background: Phosphodiesterases 9A (PDE9A) is one of the prominent regulating enzymes of the signal transduction pathway having highest catalytic affinity for second messenger, cGMP. When the cGMP level is lowered, an uncontrolled expression of PDE9A may lead to various neurodegenerative diseases. To regulate the catalytic activity of PDE9A, potent inhibitors are needed. Objective: The primary objective of the present study was to develop new xanthine based inhibitors targeting PDE9A. This study was an attempt to bring structural diversification in PDE9A inhibitor development because most of the existing inhibitors are constructed over pyrazolopyrimidinone scaffold. Methods: Manual designing and parallel molecular docking approach were used for the development of xanthine derivatives. In this study, N1, N3, N9 and C8 positions of xanthine scaffold were selected as substitution sites to design 200 new compounds. Reverse docking and pharmaceutical analyses were used for final validation of most promising compounds. Results: By keeping free energy of binding cut-off of -6.0 kcal/mol, 52 compounds were screened. The compounds with substitution at N1, N3 and C8 positions of xanthine showed good occupancy in PDE9A active site pocket with a significant interaction pattern. This was further validated by screening different factors such as free energy of binding, inhibition constant and interacting active site residues in the 5Å region. Substitution at C8 position with phenyl substituent determined the inhibition affinity of compounds towards PDE9A by establishing a strong hydrophobic - hydrophobic interaction. The alkyl chain at N1 position generated selectivity of compounds towards PDE9A. The aromatic fragment at N3 position increased the binding affinity of compounds. Thus, by comparative docking study, it was found that compound 39-42 formed selective interaction towards PDE9A over other members of the PDE superfamily. Conclusion: From the present study, N1, N3 and C8 positions of xanthine were concluded as the best sites for substitution for the generation of potent PDE9A inhibitors.

Background: Due to the importance of 1,3,4-thiadiazoles and phthalimides in anticancer agents, a novel series of 1,3,4-thiadiazole-phthalimide system have been synthesized and evaluated in vitro against HT-29 and MCF-7 human cancer cell lines. Methods: The target compounds were prepared through four-step reaction and their cytotoxicities were evaluated by MTT assay. Results: The results showed that 4-nitrobenzoyl moiety containing derivatives are the most potent ones. The morphological evaluation also indicated that these compounds are apoptotic inducers. Conclusion: 4-Nitro-N-(5-((3-(1,3-dioxoisoindolin-2-yl)propyl)thio)-1,3,4-thiadiazol-2-yl)benzamide (8m) exhibits the best inhibitory effect against HT-29 and MCF-7 cell lines with IC50 values of 23.83 and 27.21 μM, respectively.

Introduction: Azo-compounds, with the general formula R-N=N-R' (where R and R' can be either aryl or alkyl groups), constitute an important class of organic dyes. Over the past decades, these compounds have attained increasing attention of the scientific community because of their immense biological as well as industrial applications. Methodology: A series of new azo-compounds was prepared starting from 4-aminophenol and 4- methoxyaniline under standard conditions. The synthesized compounds were investigated for their potential as antibacterial agents. The bacterial strains used were Escherichia coli, Streptococcus pyrogenes, Shigellasonnei, Neisseria gonorrhoeae and Staphylococcus aureus. Results and Discussion: The structures of newly synthesized compounds were established by usual spectroscopic techniques such as UV-Vis, FTIR, Mass Spectrometry and NMR spectroscopy. These results were further supported by molecular docking studies in order to confirm the binding interaction of the compounds with bacterial proteins. Furthermore, these compounds were also investigated by density functional theory calculations. The calculated band gap (E gap) of the targeted library was found between the ranges of 0.12307-13665 eV. Conclusion: In summary, we have synthesized and characterized an interesting series of azo-compounds which have potent anti-bacterial activities against several bacterial species. The experimental results were further supported by molecular docking analysis and density functional theory calculations.

Background: Research on the synthesis of anticonvulsants is still in progress as they produce adverse effects with lesser activity as well as the patients become resistant to drug therapy. 1,2,4-triazole scaffold is a resource for the synthesis of anticonvulsant agents having better pharmacological action. Virtual Screening plays an important role to achieve binding affinity, receptor and library pre-processing, docking, scoring and top scoring hits. Optimization of drug ADME parameters continues to play an important role to achieve proof of concept, and ultimately efficacy, safely in clinical trials to address unmet medical need. Objective: The aim was to design, synthesise and evaluate anticonvulsant activity of a series of 5-substituted-2-(2-(5-aryl-1H-1,2,4-triazole-3-ylthio)acetyl) hydrazine carbothioamide/ carboxamides along with their in silico properties. Methods: Derivatives of 5-substituted-2-(2-(5-phenyl-1H-1,2,4-triazol-3-ylthio)acetyl)hydrazine carboxamides/ carbothioamides were obtained by condensation of Ethyl-2-(5-aryl-1H-1,2,4-triazol- 3-ylthio)acetates with thiosemicarbazide or semicarbazide. The synthesized compounds were characterized by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (1H NMR) and mass spectrometry (MS) while their anticonvulsant activity was screened against pentylenetetrazole-induced seizure (PTZ) against diazepam as reference standard. Molecular docking (in silico) studies were performed using 4-aminobutyrateaminotransferase in order to predict possible protein-ligand interactions. Results: Among the target compounds, 3f exhibited lower activity with 50% protection. The compounds 3e and 3h showed good to moderate levels of anticonvulsant activity with 83.3% protection at 100 mg/kg. The compounds 3g and 3i showed most significant anticonvulsant activity with 100% protection at a dose of 30 mg/kg. In silico results also revealed that 3g and 3i have shown maximum binding affinity to GABA AT protein among the tested compounds. Conclusion: The synthesized compounds showed potent anticonvulsant activity. Molecular docking results should give an insight into how further modification of lead compound can be carried out for higher inhibitory activity.

Background: Tankyrases, members of PARP protein superfamily, are involved in many cellular processes and play key roles in Wnt signaling and in several diseases including cancers. During the past few years, there has been an increased interest in the development of selective smallmolecular tankyrase inhibitors. Objective: The objective was to construct a novel selective pharmacophore model for tankyrase inhibitors. Methods: In this paper, the novel selective pharmacophore model was constructed using a combination of computational methods, including molecular docking, protein-ligand interaction fingerprint (PLIF) similarity investigation, 3D-QSAR pharmacophore merging, binding site analysis like protein sequence alignment, SiteMap and FTMap. Results: Within these analyses, a novel selective pharmacophore model was constructed. The two HY features were located in the induced pocket and the sub-pocket, respectively. The hydrogen bond acceptor (HBA) feature corresponding to Tyr1213 was located in the sub-pocket. To assess the reliability and validity of the pharmacophore, the model was then applied to screen two validation databases for highly selective tankyrase inhibitors. The high values of enrichment factor (32.61; 34.52) and receiver operating characteristic (ROC) score (0.853; 0.805) indicated the model performed fairly well at distinguishing the selective tankyrase inhibitors from putative inactive compounds. Furthermore, 12 highly selective inhibitors (10000-fold) were all ranked in the forefront of screening results. Conclusion: The pharmacophore model reflects the most important binding requirements for the selective tankyrase inhibitors, and the results can provide new insights for design and discovery of novel tankyrase inhibitors with high selectivity.

Background: Acetic acid alone when employed as a solvent under ultrasound irradiation has been found to be effective for the three-component reaction involving ethyl-5- amino-1H-pyrazole-4-carboxylate, aromatic aldehydes and terminal alkynes in the presence of aerial oxygen. Methods: The catalyst / promoter / ligand free method afforded a range of pyrazolo[1,5-a] pyrimidines as potential and new cytotoxic agents. Results and Conclusion: While some of these compounds showed cytotoxicities against two breast cancer cell lines one of them was found to be promising.

Background: The ultrasound assisted methodology has been explored first time for the quicker synthesis of 6H-pyrido[1,2-a]quinazolin-6-imine derivatives via the reaction of 2-aminopyridines and 2-fluorobenzontriles under mild conditions. Methods: The methodology is free from the use of any transition metal catalyst and afforded the desired products in good yields. Some of the synthesized compounds were evaluated for their potential PDE4 inhibition in silico and subsequently in vitro. Conclusion: One compound showed dose dependent inhibition of PDE4B and favorable pharmacological properties indicating potential of this scaffold for the discovery of new inhibitors of PDE4.

Background: The molecular hybridization concept was used to develop novel coupled derivatives with the hope of synergistic cytotoxic activity. A novel class of 12 derivatives, containing coupled 7-oxycoumarin, piperazine, and heteryl/ aryl propenone moieties namely, 4-methyl-7- (3-(4-methylpiperazin-1-yl)-3-oxo-1-substituted phenyl/heteryl prop-1-en-2-yloxy)-2h-chromen-2- ones were synthesized by an ultrasound-assisted, eco-friendly protocol. Methods: All the designed hybrids were evaluated for their in vitro cytotoxic activity against a panel of three human cancer cell lines viz MCF-7 (human breast cancer cell line), HeLa (human cervical cancer cell line), NCI-H226 (non-small cell lung cancer cell line). Most of the compounds exhibited promising cytotoxicity; some compounds have shown GI50 values similar to that of the standard drug, Adriamycin. Compounds 4d, 4b, and 4a were found to be the most promising cytotoxic derivatives in this study. Results: Molecular docking study was performed to support the effective binding of compounds at the active site of the enzyme and to know the binding mode of synthesized compounds for inhibition of topoisomarase II. Further, the compounds docking results against topoisomerase-II were in good agreement with the observed GI50 values. Conclusion: A computational study was performed for prediction of ADME properties and it was observed that the compounds exhibited good % absorption; all the tested compounds 4(a-l) followed the criteria for an orally active drug and, therefore, these compounds can have a good potential for eventual development as oral agents.

Background: The 2-alkynyl pyrazolo[1,5-a]pyrimidine derivatives have been explored as new and potential anti-proliferative agents. Methods: Ultrasound assisted synthesis of these compounds was carried out by using a multi-step method involving the H3PO3 mediated construction of pyrazolo[1,5-a]pyrimidine ring possessing a bromo group at C-2 position followed by Pd/C-Cu catalyzed alkynylation methodology as the key steps. Results and Conclusion: All these compounds showed selective growth inhibition of cancer cell lines when tested against MDA-MB 231 and K562 cell lines along with non-cancerous HEK293 cells.

Background: Argireline is an innovative neuropeptide widely applied topically on the skin. Its structure resembles the N-terminal end of the synaptic protein SNAP-25, and so inhibits the formation of SNARE complex and reduces the release of the neurotransmitter acetylcholine. These properties are used in cosmetic formulations to reduce facial muscle contractions, thus preventing the formation of expressive wrinkles, mainly on the forehead and around eyes. Methodology: Argireline is a biomimetic peptide whose effect has been confirmed. When used at a concentration of 5-10%, its therapeutic activity is similar to that of botulinum toxin but without its side effects. This biologically-active ingredient is used for daily home care (good penetration of emulsion W/O/W) and in beauty salons to facilitate penetration of peptides through the skin (dermarollery, iontophoresis). Conclusion: The article presents recent data concerning the value of argireline as a highly important synthetic molecule which affects the mechanical properties of the skin.

Objective: To explore the function of p42.3 in gastric carcinoma. Methods: We summarized the intricate regulation of p42.3 in gastric carcinoma from several aspects, namely, the structure features, the expression level, its regulation on cell cycle and EMT, its relationship with miR-29a as well as the optimal feedback circuit involved in. Results: We addressed the complex functions of p42.3 in regulating EMT, migration, invasion, proliferation and the optimal regulation network in GC, as well as the significant up/down-stream signal molecules involved in the pathway. We have also illuminated that miR-29a can inhibit cell proliferation and block the cell cycle, at least in part, via the repression of p42.3. Conclusion: In short, p42.3 might serve as a potential therapeutic target in the treatment of GC.