Systematic analysis of molecular mechanism of resveratrol for treating pulmonary hypertension based on network pharmacology technology.

Resveratrol is a polyphenolic antioxidant derived from plant products such as grapes. Previous studies explored the effects of resveratrol on pulmonary hypertension (PH). However, systematic research on the exact mechanism of action of resveratrol is still lacking; in particular, our knowledge on the molecule-gene interaction is limited. In this study, systematic pharmacology and bioinformatic approaches were employed to identify the potential targets of resveratrol for treating PH. Furthermore, core genes were identified by constructing a protein-protein interaction network and by conducting topology analyses. The results showed that the effect of resveratrol may be closely associated with targets such as AKT serine/threonine kinase 1 (AKT1), mitogen-activated protein kinase 3 (MAPK3), Sirtuin-1 (SIRT1) and proto-oncogene tyrosine-protein kinase Src (SRC), as well as biological processes such as cell proliferation, inflammatory response, and redox balance. The present study systematically elucidates the mechanisms by which resveratrol alleviates PH and provides a new perspective on drug research for this disease.

Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic.

Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.

In-Silico Screening of Ligand Based Pharmacophore, Database Mining and Molecular Docking on 2, 5-Diaminopyrimidines Azapurines as Potential Inhibitors of Glycogen Synthase Kinase-3ß.

BACKGROUND: Glycogen synthase kinase-3ß plays a significant role in the regulation of various pathological pathways relating to the Central Nervous System (CNS). Dysregulation of Glycogen synthase kinase 3 (GSK-3) activity gives rise to numerous neuroinflammation and neurodegenerative related disorders that affect the whole central nervous system. OBJECTIVE: By the sequential application of in-silico tools, efforts have been attempted to design the novel GSK-3ß inhibitors. METHOD: Owing to the potential role of GSK-3ß in nervous disorders, we have attempted to develop the quantitative four featured pharmacophore model comprising two Hydrogen Bond Acceptors (HBA), one Ring Aromatic (RA), and one Hydrophobe (HY), which were further affirmed by costfunction analysis, rm2 matrices, internal and external test set validation and Guner-Henry (GH) scoring analysis. Validated pharmacophoric model was used for virtual screening and out of 345 compounds, two potential virtual hits were finalized that were on the basis of fit value, estimated activity and Lipinski's violation. The chosen compounds were subjected to dock within the active site of GSK-3ß. RESULT: Four essential features, i.e., two Hydrogen Bond Acceptors (HBA), one Ring Aromatic (RA), and one Hydrophobe (HY), were subjected to build the pharmacophoric model and showed good correlation coefficient, RMSD and cost difference values of 0.91, 0.94 and 42.9 respectively and further model was validated employing cost-function analysis, rm2-matrices, internal and external test set prediction with r2 value of 0.77 and 0.84. Docked conformations showed potential interactions in between the features of the identified hits (NCI 4296, NCI 3034) and the amino acids present in the active site. CONCLUSION: In line with the overhead discussion, and through our stepwise computational approaches, we have identified novel, structurally diverse glycogen synthase kinase inhibitors.

Evolving Strategies for the Treatment of T-Cell Lymphoma: A Systematic Review and Recent Patents.

OBJECTIVE: Mature T-cell lymphomas are a heterogeneous group of T-cell malignancies with a poor outcome. The discovery of new molecular biomarkers has led to the emergence of new drugs in recent years that target various signaling pathways. METHODS: We examined all pertinent published patents through 2015 that analyzed novel methods for the diagnosis and treatment of T cell lymphoma, as well as related published and unpublished studies. Selection criteria were established before data collection. An exhaustive literature search was performed using MEDLINE and Science Direct databases. The search criteria were T-cell lymphoma, diagnosis, and treatment. RESULTS: Recent papers have identified recurrent epigenetic factor mutations in RHOA and FYN kinase in PTCL allowing new perspectives for epigenetic-based therapy, molecular classification model using CD28, ABCA5 transporter, coiled-coil domain-containing protein 3, and angiogenic factor SMOC2 biomarkers for differentiating forms of lymphomas, as well as expression of receptors forTNFR-1, TNFR-2, and IL12p40/70 in CTCL. New therapeutic targets have been reported such as MicroRNAs - 155 inhibitors and synthetic Toll-Like Receptor 7/8 agonists for treating CTCL, Anti CTLA-4 antibodies, anti- Killer cell immunoglobulin-like receptors 3DL2 and NK-p46 (NCR receptors) antibodies for treating PTCL, Cd1d antagonist-restricted gamma/delta-T cell lymphomas, antiEZH2, novel antihistone deacetylase, and NK cells engineered therapy. In the transplantation setting, the objective was to eradicate overcoming of the residual disease immunity and to induce an immune tolerance by anti-third part cells with a central memory T-lymphocyte phenotype. CONCLUSION: Therapeutic strategies based on a better molecular characterization of various histological types are certain to be used in the future.

Homology Modeling and Molecular Docking Studies of Bacillomycin and Iturin Synthetases with Novel Ligands for the Production of Therapeutic Lipopeptides.

BACKGROUND: Lipopeptide synthetases play an important role in the production of lipopeptides. Lipopeptides are molecules made up of peptides and fatty acid moieties and have shown to have a broad range of antimicrobial activity. As infectious diseases have caused severe health problems mainly resulting from the development of antibiotic resistant strains of disease causing microorganisms there is a need of alternatives to antibiotics. The lipopeptide synthetase of the corresponding lipopeptides can be used as template to design these as drugs using computational techniques. OBJECTIVE: The objective of this study was homology modeling and molecular docking of two lipopeptide synthetases, bacillomycin D synthetase and iturin A synthetase, with their ligands as a means of drug design. METHOD: Schrödinger software was used for homology modeling and molecular docking. RESULTS: After the identification of ligands, molecular docking of these ligands with the lipopeptide (bacillomycin and iturin) synthetases was performed. The docking was tested on the parameters of docking score and glide energy. 5 out of 21 ligands were found to dock with bacillomycin D synthetase whereas 8 out of 20 ligands docked with the iturin A synthetase. CONCLUSION: The knowledge of the docking sites and docking characteristics of the lipopeptide synthetases mentioned in the paper with the ligands can provide advantages of high speed and reliability, reduced costs on chemicals and experiments and the ethical issues concerned with the use of animal models for screening of drug toxicity.

Poly-glutamic dendrimer-based conjugates for cancer vaccination - a computational design for targeted delivery of antigens.

Computational techniques are useful to predict interaction models and molecular properties for the design of drug delivery systems, such as dendrimers. This work evaluated the impact of surface modifications of mannosamine-conjugated multifunctional poly(glutamic acid) (PG)-dendrimers as nanocarriers of the tumour associated antigens (TAA) MART-1, gp100:44 and gp100:209. Molecular dynamics simulations and docking studies were performed. Nitrobenzoxadiazole (NBD)-PG-G4-dendrimer displayed 64 carboxylic groups, however, the Frontier Molecular Orbital Theory study evidenced that only 32 of those were available to form covalent bonds. When the number of mannosamines conjugated to dendrimer was increased from 16 to 32, the dendrimer interacted with the receptor with higher affinity. However, 16 mannosamines-NBD-PG-G4-dendrimer was chosen to conjugate TAA for added functionality as no carboxylic end groups were available for further conjugation in the 32 mannosamines-dendrimer. Docking results showed that the majority of TAA-conjugated NBD-PG-G4-dendrimer demonstrated a favourable interaction with mannosamine binding site on mannose receptor, thus constituting a promising tool for TAA targeted delivery. Our in silico approach effectively narrows down the selection of the best candidates for the synthesis of functionalised PG-dendrimers with desired functionalities. These results will significantly reduce the time and efforts required to experimentally synthesise modified dendrimers for optimal antigen delivery.

Design strategies of oxidosqualene cyclase inhibitors: Targeting the sterol biosynthetic pathway.

Targeting the sterol biosynthesis pathway has been explored for the development of new bioactive compounds. Among the enzymes of this pathway, oxidosqualene cyclase (OSC) which catalyzes lanosterol cyclization from 2,3-oxidosqualene has emerged as an attractive target. In this work, we reviewed the most promising OSC inhibitors from different organisms and their potential for the development of new antiparasitic, antifungal, hypocholesterolemic and anticancer drugs. Different strategies have been adopted for the discovery of new OSC inhibitors, such as structural modifications of the natural substrate or the reaction intermediates, the use of the enzyme's structural information to discover compounds with novel chemotypes, modifications of known inhibitors and the use of molecular modeling techniques such as docking and virtual screening to search for new inhibitors. This review brings new perspectives on structural insights of OSC from different organisms and reveals the broad structural diversity of OSC inhibitors which may help evidence lead compounds for further investigations with various therapeutic applications.

Virtual screening applications in short-chain dehydrogenase/reductase research.

Several members of the short-chain dehydrogenase/reductase (SDR) enzyme family play fundamental roles in adrenal and gonadal steroidogenesis as well as in the metabolism of steroids, oxysterols, bile acids, and retinoids in peripheral tissues, thereby controlling the local activation of their cognate receptors. Some of these SDRs are considered as promising therapeutic targets, for example to treat estrogen-/androgen-dependent and corticosteroid-related diseases, whereas others are considered as anti-targets as their inhibition may lead to disturbances of endocrine functions, thereby contributing to the development and progression of diseases. Nevertheless, the physiological functions of about half of all SDR members are still unknown. In this respect, in silico tools are highly valuable in drug discovery for lead molecule identification, in toxicology screenings to facilitate the identification of hazardous chemicals, and in fundamental research for substrate identification and enzyme characterization. Regarding SDRs, computational methods have been employed for a variety of applications including drug discovery, enzyme characterization and substrate identification, as well as identification of potential endocrine disrupting chemicals (EDC). This review provides an overview of the efforts undertaken in the field of virtual screening supported identification of bioactive molecules in SDR research. In addition, it presents an outlook and addresses the opportunities and limitations of computational modeling and in vitro validation methods.