GPCR-IPL score: multilevel featurization of GPCR-ligand interaction patterns and prediction of ligand functions from selectivity to biased activation.

G-protein-coupled receptors (GPCRs) mediate diverse cell signaling cascades after recognizing extracellular ligands. Despite the successful history of known GPCR drugs, a lack of mechanistic insight into GPCR challenges both the deorphanization of some GPCRs and optimization of the structure-activity relationship of their ligands. Notably, replacing a small substituent on a GPCR ligand can significantly alter extracellular GPCR-ligand interaction patterns and motion of transmembrane helices in turn to occur post-binding events of the ligand.

Positioning of an unprecedented 1,5-oxaza spiroquinone scaffold into SMYD2 inhibitors in epigenetic space.

Lysine methyltransferases are important regulators of epigenetic signaling and are emerging as a novel drug target for drug discovery. This work demonstrates the positioning of novel 1,5-oxaza spiroquinone scaffold into selective SET and MYND domain-containing proteins 2 methyltransferases inhibitors. Selectivity of the scaffold was identified by epigenetic target screening followed by SAR study for the scaffold.

In silico identification of prolyl hydroxylase inhibitor by per-residue energy decomposition-based pharmacophore approach.

Hypoxia is an effective preconditioning stimulus and many cellular responses to hypoxia are mediated through a transcription control complex termed the hypoxia-inducible factor (HIF). The stability and activation of HIF are governed by HIF prolyl-4-hydroxylases 2 (PHD2). Hence, the development of a small molecule inhibitor for prolyl hydroxylase has been suggested as a potentially useful therapeutic strategy for the treatment of oxidative/ischemic stress conditions.

Positioning of an unprecedented spiro[5.5]undeca ring system into kinase inhibitor space.

In-house 1,5-oxaza spiroquinone 1, with spiro[5.5]undeca ring system, was announced as an unprecedented anti-inflammatory scaffold through chemistry-oriented synthesis (ChOS), a chemocentric approach. Herein, we studied how to best position the spiro[5.

identification of hydantoin derivatives: a novel natural prolyl hydroxylase inhibitor.

Alzheimer's disease (AD) is the most common dementia in late life memory related issues. It is estimated that worldwide 46.8 million people suffer from dementia.

Ligand-based pharmacophore modeling and docking studies on vitamin D receptor inhibitors.

In recent years, pharmacophore modeling and molecular docking approaches have been extensively used to characterize the structural requirements and explore the conformational space of a ligand in the binding pocket of the selected target protein. Herein, we report a pharmacophore modeling and molecular docking of 45 compounds comprising of the indole scaffold as vitamin D receptor (VDR) inhibitors. Based on the selected best hypothesis (DRRRR.

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization.

Isorhapontigenin (ISO), a tetrahydroxylated stilbenoid, is an analog of resveratrol (Rsv). The various biological activities of Rsv and its derivatives have been previously reported in the context of both cancer and inflammation. However, the anti-cancer effect of ISO against breast cancer has not been well established, despite being an orally bioavailable dietary polyphenol.

Molecular Targets for Malarial Chemotherapy: A Review.

The malaria parasite resistance to the existing drugs is a serious problem to the currently used antimalarials and, thus, highlights the urgent need to develop new and effective anti-malarial molecules. This could be achieved either by the identification of the new drugs for the validated targets or by further refining/improving the existing antimalarials; or by combining previously effective agents with new/existing drugs to have a synergistic effect that counters parasite resistance; or by identifying novel targets for the malarial chemotherapy. In this review article, a comprehensive collection of some of the novel molecular targets has been enlisted for the antimalarial drugs.

β-N-oxalyl-L-α, β- diaminopropionic acid induces HRE expression by inhibiting HIF-prolyl hydroxylase-2 in normoxic conditions.

Hypoxia inducible factor (HIF)-1α, a subunit of HIF transcription factor, regulates cellular response to hypoxia. In normoxic conditions, it is hydroxylated by prolyl hydroxylase (PHD)-2 and targeted for proteosomal degradation. Drugs which inhibit PHD-2 have implications in conditions arising from insufficient blood supply.

Post-stroke transplantation of adult subventricular zone derived neural progenitor cells--A comprehensive analysis of cell delivery routes and their underlying mechanisms.

With neuroprotective approaches having failed until recently, current focus on experimental stroke research has switched towards manipulation of post-ischemic neuroregeneration. Transplantation of subventricular zone (SVZ) derived neural progenitor cells (NPCs) is a promising strategy for promotion of neurological recovery. Yet, fundamental questions including the optimal cell delivery route still have to be addressed.

Computational repositioning and experimental validation of approved drugs for HIF-prolyl hydroxylase inhibition.

HIF stability and activation are governed by a family of dioxygenases called HIF prolyl-4-hydroxylases (PHDs). It has been identified as a new target to augment the adaptive machinery that governs cytoprotection in disorders associated with ischemia/reperfusion, inflammation, and oxidative stress. In this sense, PHD inhibition has been proposed to mimic, at least in part, the protective effects of exposure to hypoxia.

Pharmacophore generation and atom-based 3D-QSAR of N-iso-propyl pyrrole-based derivatives as HMG-CoA reductase inhibitors.

Background: Coronary heart disease continues to be the leading cause of mortality and a significant cause of morbidity and account for nearly 30% of all deaths each year worldwide. High levels of cholesterol are an important risk factor for coronary heart disease. The blockage of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity by small molecule inhibitors has been shown to inhibit hypercholesterolemia.

A combination of 3D-QSAR modeling and molecular docking approach for the discovery of potential HIF prolyl hydroxylase inhibitors.

Suppression of HIF prolyl hydroxylase (PHD) activity by small molecule inhibitors leads to the stabilization of HIF and offers a potential therapeutic option for treating ischemic disorders. In this study, pharmacophore based QSAR modeling, virtual screening and molecular docking approaches were concurrently used to identify target-specific PHD inhibitors with better ADME properties and to readily minimize false positives and false negatives. A 3D-QSAR based method was used to generate a pharmacophore hypothesis (AAAN).

Generation of pharmacophore and atom based 3D-QSAR model of novel isoquinolin-1-one and quinazolin-4-one-type inhibitors of TNFα.

In the present report, 3D-QSAR analysis was executed on the previously synthesized and evaluated derivatives of isoquinolin-1-ones and quinazolin-4-ones; potent inhibitors of tumor necrosis factor α (TNFα). Statistically significant 3D-QSAR models were generated using 42 molecules in the training set. The predictive ability of models was determined using a randomly chosen test set of 16 molecules, which gave excellent predictive correlation coefficients for 3-D models, suggesting good predictive index.

Computational identification of novel histone deacetylase inhibitors by docking based QSAR.

Histone deacetylases (HDACs) are enzymes that modify chromatin structure and contribute to aberrant gene expression in cancer. A series compounds with well-assigned HDAC inhibitory activity was used for docking based 3D-QSAR analysis. The 3D-QSAR acquired had excellent correlation coefficient value (q2=0.

Identification of novel potential HIF-prolyl hydroxylase inhibitors by in silico screening.

Suppression of HIF-prolyl hydroxylase (PHD) activity by small-molecule inhibitors leads to the stabilization of hypoxia inducible factor and has been recognized as promising drug target for the treatment of ischemic diseases. In this study, pharmacophore-based virtual screening and molecular docking approaches were concurrently used with suitable modifications to identify target-specific PHD inhibitors with better absorption, distribution, metabolism, and excretion properties and to readily minimize false positives and false negatives. A customized method based on the active site information of the enzyme was used to generate a pharmacophore hypothesis (AAANR).

Pharmacophore generation and atom-based 3D-QSAR of novel quinoline-3-carbonitrile derivatives as Tpl2 kinase inhibitors.

Tumour progression locus-2 (Tpl2) is a serine/threonine kinase, which regulates the expression of tumour necrosis factor α. The article describes the development of a robust pharmacophore model and the investigation of structure-activity relationship analysis of quinoline-3-carbonitrile derivatives reported for Tpl2 kinase inhibition. A five point pharmacophore model (ADRRR) was developed and used to derive a predictive atom-based 3-dimensional quantitative structure activity relationship (3D-QSAR) model.

Nanotechnology and nanomedicine: going small means aiming big.

Nanotechnology is an emerging branch of science for designing tools and devices of size 1 to 100 nm with specific function at the cellular, atomic and molecular levels. The concept of employing nanotechnology in biomedical research and clinical practice is best known as nanomedicine. Nanomedicine is an upcoming field that could potentially make a major impact to human health.