Allosteric regulation of DNA binding and target residence time drive the cytotoxicity of phthalazinone-based PARP-1 inhibitors.

Allosteric coupling between the DNA binding site to the NAD-binding pocket drives PARP-1 activation. This allosteric communication occurs in the reverse direction such that NAD mimetics can enhance PARP-1's affinity for DNA, referred to as type I inhibition. The cellular effects of type I inhibition are unknown, largely because of the lack of potent, membrane-permeable type I inhibitors.

A Cancer Cell-Intrinsic GOT2-PPARδ Axis Suppresses Antitumor Immunity.

Unlabelled: Despite significant recent advances in precision medicine, pancreatic ductal adenocarcinoma (PDAC) remains near uniformly lethal. Although immune-modulatory therapies hold promise to meaningfully improve outcomes for patients with PDAC, the development of such therapies requires an improved understanding of the immune evasion mechanisms that characterize the PDAC microenvironment. Here, we show that cancer cell-intrinsic glutamic-oxaloacetic transaminase 2 (GOT2) shapes the immune microenvironment to suppress antitumor immunity.

Control of coronary vascular resistance by eicosanoids via a novel GPCR.

Arachidonic acid metabolites epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs) are important regulators of myocardial blood flow and coronary vascular resistance (CVR), but their mechanisms of action are not fully understood. We applied a chemoproteomics strategy using a clickable photoaffinity probe to identify G protein-coupled receptor 39 (GPR39) as a microvascular smooth muscle cell (mVSMC) receptor selective for two endogenous eicosanoids, 15-HETE and 14,15-EET, which act on the receptor to oppose each other's activity. The former increases mVSMC intracellular calcium via GPR39 and augments coronary microvascular resistance, and the latter inhibits these actions.

Extraction of Fucoidan from and the Synthesis of Fucoidan-Coated AgNPs for Anticoagulant Application.

Brown seaweeds usually contain alginate as a major polymer. The second major sulfated polymer in brown seaweeds is fucoidan, which has huge potential in medicinal applications. In this study, the photosynthetic pigments from were first extracted using chloroform/methanol in the ratio of 1:1 (v/v), followed by fucoidan extraction with yields of 5.

Mapping the Molecular Architecture Required for Lipid-Binding Pockets Using a Subset of Established and Orphan G-Protein Coupled Receptors.

G-protein coupled receptors (GPCRs) sense a wide variety of stimuli, including lipids, and transduce signals to the intracellular environment to exert various physiological responses. However, the structural features of GPCRs responsible for detecting and triggering responses to distinct lipid ligands have only recently begun to be revealed. 14,15-epoxyeicosatrienoic acid (14,15-EET) is one such lipid mediator that plays an essential role in the vascular system, displaying both vasodilatory and anti-inflammatory properties.

Affinity, potency, efficacy, selectivity, and molecular modeling of substituted fentanyls at opioid receptors.

Substituted fentanyls are abused and cause rapid fatal overdose. As their pharmacology is not well characterized, we examined in vitro pharmacology and structure-activity relationships of 22 substituted fentanyls with modifications of the fentanyl propyl group, and conducted in silico receptor/ligand modeling. Affinities for mu, kappa, and delta opioid receptors (MOR, KOR, and DOR, respectively) heterologously expressed in mammalian cells were assessed in agonist radioligand binding assays.

Ranolazine may exert its beneficial effects by increasing myocardial adenosine levels.

We hypothesized that ranolazine-induced adenosine release is responsible for its beneficial effects in ischemic heart disease. Sixteen open-chest anesthetized dogs with noncritical coronary stenosis were studied at rest, during dobutamine stress, and during dobutamine stress with ranolazine. Six additional dogs without stenosis were studied only at rest.

Effect of thermostable mutations on the neurotensin receptor 1 (NTSR) activation state.

Neurotensin (NTS) is a 13-amino acid neuropeptide with neuroendocrine and vasoactive functions that is widely expressed in the central nervous system and gastrointestinal tract. NTS is sensed by a multiple cell surface proteins including two G protein-coupling receptors (GPCRs): NTS receptors 1 and 2 (NTSR and NTSR). Crystal structures of NTSR have successfully elucidated agonist binding within the orthosteric pocket of receptor but have not revealed the full activation state of the receptor.

Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters.

Rationale: New psychoactive substances (NPSs), including substituted cathinones and other stimulants, are synthesized, sold on the Internet, and ingested without knowledge of their pharmacological activity and/or toxicity. In vitro pharmacology plays a role in therapeutic drug development, drug-protein in silico interaction modeling, and drug scheduling.

Objectives: The goal of this research was to determine mechanisms of action that may indicate NPS abuse liability.

Exploring a potential allosteric inhibition mechanism in the motor domain of human Eg-5.

Kinesin-5 (Eg-5), microtubule motor protein, is one of the emerging drug targets in cancer research. Several inhibitors have been reported to bind the hEg-5 "motor domain" in two different locations that are potentially allosteric. Interestingly, the crystal structure of Eg-5 bound to benzimidazole unveils two chemically different allosteric pockets (PDB ID: 3ZCW).

Tubulin inhibitor identification by bioactive conformation alignment pharmacophore-guided virtual screening.

Microtubules are important cellular component that are critical for proper cellular function. Microtubules are synthesized by polymerization of αβ tubulin heterodimers called protofilaments. Microtubule dynamics facilitate proper cell division during mitosis.

Receptor-ligand interaction-based virtual screening for novel Eg5/kinesin spindle protein inhibitors.

Eg5/KSP is a promising mitotic spindle target for drug discovery in cancer chemotherapy and the development of agents against fungal diseases. A range of Eg5 targeting compounds identified by in vitro or cell-based screening is currently in development. We employed structure-based virtual screening of a database of 700, 000 compounds to identify three novel Eg5 inhibitors bearing quinazoline (24) or thioxoimidazolidine (30 and 37) scaffolds.

Homology modeling, molecular dynamics, e-pharmacophore mapping and docking study of Chikungunya virus nsP2 protease.

To date, no suitable vaccine or specific antiviral drug is available to treat Chikungunya viral (CHIKV) fever. Hence, it is essential to identify drug candidates that could potentially impede CHIKV infection. Here, we present the development of a homology model of nsP2 protein based on the crystal structure of the nsP2 protein of Venezuelan equine encephalitis virus (VEEV).

IKKβ inhibitor identification: a multi-filter driven novel scaffold.

Background: Nuclear factor kappa B (NF-κB) is a chief nuclear transcription factor that controls the transcription of various genes; and its activation is tightly controlled by Inhibitor kappa B kinase (IKK). The irregular transcription of NF-κB has been linked to auto-immune disorders, cancer and other diseases. The IKK complex is composed of three units, IKKα, IKKβ, and the regulatory domain NEMO, of which IKKβ is well understood in the canonical pathway.

IKKbeta inhibitors identification part II: ligand and structure-based virtual screening.

IkappaB kinase (IKK) is critical in proinflammatory cytokine-induced IkappaBalpha phosphorylation and subsequent activation of the nuclear transcription factor NF-kappaB complex. The activated NF-kappaB plays a major role in the pathogenesis of a number of human disorders, such as rheumatic and chronic inflammatory diseases. The inhibition of NF-kappaB activation by small molecule inhibitors that targets IKKbeta may provide a pharmacological basis for interfering with these acute processes.

3D QSAR pharmacophore model based on diverse IKKβ inhibitors.

The inhibitor kappaB kinase β (IKKβ) is a serine-threonine protein kinase that is critically involved in the activation of the transcription factor nuclear factor kappa B (NF-κB) in response to various inflammatory stimuli. IKKβ-selective inhibitors could prove useful for the treatment of inflammatory diseases. In the absence of structural information, a ligand-based approach can serve as an alternative to the virtual screening of large databases.

New structural insights and molecular-modelling studies of 4-methyl-5-beta-hydroxyethylthiazole kinase from Pyrococcus horikoshii OT3 (PhThiK).

4-Methyl-5-beta-hydroxyethylthiazole kinase (ThiK) catalyses the phosphorylation of the hydroxyl group of 4-methyl-5-beta-hydroxyethylthiazole. This work reports the first crystal structure of an archaeal ThiK: that from Pyrococcus horikoshii OT3 (PhThiK) at 1.85 A resolution with a phosphate ion occupying the position of the beta-phosphate of the nucleotide.

IKKbeta inhibitors identification part I: homology model assisted structure based virtual screening.

Control of NF-kappaB release through the inhibition of IKKbeta has been identified as a potential target for the treatment of inflammatory and autoimmune diseases. We have employed structure based virtual screening scheme to identify lead like molecule from ChemDiv database. Homology models of IKKbeta enzyme were developed based on the crystal structures of four kinases.

DrugMetZ DB: an anthology of human drug metabolizing Chytochrome P450 enzymes.

Unlabelled: Understandings the basics of Cytochrome P450 (P450 or CYP) will help to discern drug metabolism. CYP, a super-family of heme-thiolate proteins, are found in almost all living organisms and is involved in the biotransformation of a diverse range of xenobiotics, therapeutic drugs and toxins. Here, we describe DrugMetZ DB, a database for CYP metabolizing drugs.

Binding site prediction of galanin peptide using evolutionary trace method.

Galanin is a neuropeptide with aminoacid length ranging from 29 to 31 is widely distributed in central and peripheral nervous system. Galanin controls various psychological processes such as sensation of pain, learning, feeding, and sexual behaviour. The N-terminal region of this neuropeptide has highly conserved 15 amino acids, which is triggered by galanin receptors.