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Structure-based discovery of natural-product-like TNF-? inhibitors.

ABSTRACT: Small but effective: two natural-product-like inhibitors of tumor necrosis factor?? (TNF-?; represented in green in the picture) have been identified using structure-based virtual screening. These compounds represent only the third and fourth examples of direct targeting of TNF-? by a small molecule, and display potency comparable to that of the strongest TNF-? inhibitor reported to date.

SUBMITTER: Chan DS

PROVIDER: S-EPMC4162403 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Structure-based discovery of natural-product-like TNF-α inhibitors.

Chan Daniel Shiu-Hin DS Lee Ho-Man HM Yang Fang F Che Chi-Ming CM Wong Catherine C L CC Abagyan Ruben R Leung Chung-Hang CH Ma Dik-Lung DL

Angewandte Chemie (International ed. in English) 20100316 16

Small but effective: two natural-product-like inhibitors of tumor necrosis factor α (TNF-α; represented in green in the picture) have been identified using structure-based virtual screening. These compounds represent only the third and fourth examples of direct targeting of TNF-α by a small molecule, and display potency comparable to that of the strongest TNF-α inhibitor reported to date. ...[more]

PMID: 20235259

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Cheminformatics in Natural Product-based Drug Discovery.

Project description:This review seeks to provide a timely survey of the scope and limitations of cheminformatics methods in natural product-based drug discovery. Following an overview of data resources of chemical, biological and structural information on natural products, we discuss, among other aspects, in silico methods for (i) data curation and natural products dereplication, (ii) analysis, visualization, navigation and comparison of the chemical space, (iii) quantification of natural product-likeness, (iv) prediction of the bioactivities (virtual screening, target prediction), ADME and safety profiles (toxicity) of natural products, (v) natural products-inspired de novo design and (vi) prediction of natural products prone to cause interference with biological assays. Among the many methods discussed are rule-based, similarity-based, shape-based, pharmacophore-based and network-based approaches, docking and machine learning methods.

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Botulinum neurotoxin A protease: discovery of natural product exosite inhibitors.

Project description:A new mechanistic class of BoNT/A zinc metalloprotease inhibitors, from Echinacea, exemplified by the natural product d-chicoric acid (I1) is disclosed. A detailed evaluation of chicoric acid's mechanism of inhibition reveals that the inhibitor binds to an exosite, displays noncompetitive partial inhibition, and is synergistic with a competitive active site inhibitor when used in combination. Other components found in Echinacea, I3 and I4, were also inhibitors of the protease.

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Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO-1) Inhibitors Based on Ortho-Naphthaquinone-Containing Natural Product.

Project description:There is great interest in developing small molecules agents capable of reversing tumor immune escape to restore the body's immune system. As an immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO-1) is considered a promising target for oncology immunotherapy. Currently, none of IDO-1 inhibitors have been launched for clinical practice yet. Thus, the discovery of new IDO-1 inhibitors is still in great demand. Herein, a series of diverse ortho-naphthaquinone containing natural product derivatives were synthesized as novel IDO-1 inhibitors. Among them, 1-ene-3-ketone-17-hydroxyl derivative 12 exhibited significantly improved enzymatic and cellular inhibitory activity against IDO-1 when compared to initial lead compounds. Besides, the molecular docking study disclosed that the two most potent compounds 11 and 12 have more interactions within the binding pocket of IDO-1 via hydrogen-bonding, which may account for their higher IDO-1 inhibitory activity.

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Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?

Project description:High-throughput biology has contributed a wealth of data on chemicals, including natural products (NPs). Recently, attention was drawn to certain, predominantly synthetic, compounds that are responsible for disproportionate percentages of hits but are false actives. Spurious bioassay interference led to their designation as pan-assay interference compounds (PAINS). NPs lack comparable scrutiny, which this study aims to rectify. Systematic mining of 80+ years of the phytochemistry and biology literature, using the NAPRALERT database, revealed that only 39 compounds represent the NPs most reported by occurrence, activity, and distinct activity. Over 50% are not explained by phenomena known for synthetic libraries, and all had manifold ascribed bioactivities, designating them as invalid metabolic panaceas (IMPs). Cumulative distributions of ?200,000 NPs uncovered that NP research follows power-law characteristics typical for behavioral phenomena. Projection into occurrence-bioactivity-effort space produces the hyperbolic black hole of NPs, where IMPs populate the high-effort base.

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In Silico Discovery of Plant-Origin Natural Product Inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-?B Ligand (RANKL).

Project description:An in silico drug discovery pipeline for the virtual screening of plant-origin natural products (NPs) was developed to explore new direct inhibitors of TNF and its close relative receptor activator of nuclear factor kappa-B ligand (RANKL), both representing attractive therapeutic targets for many chronic inflammatory conditions. Direct TNF inhibition through identification of potent small molecules is a highly desired goal; however, it is often hampered by severe limitations. Our approach yielded a priority list of 15 NPs as potential direct TNF inhibitors that were subsequently tested in vitro against TNF and RANKL. We thus identified two potent direct inhibitors of TNF function with low micromolar IC50 values and minimal toxicity even at high concentrations. Most importantly, one of them (A11) was proved to be a dual inhibitor of both TNF and RANKL. Extended molecular dynamics simulations with the fully automated EnalosMD suite rationalized the mode of action of the compounds at the molecular level. To our knowledge, these compounds constitute the first NP TNF inhibitors, one of which being the first NP small-molecule dual inhibitor of TNF and RANKL, and could serve as lead compounds for the development of novel treatments for inflammatory and autoimmune diseases.

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Proteomics-based discovery of koranimine, a cyclic imine natural product.

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Discovery of Natural Product Derived Labdane Appended Triazoles as Potent Pancreatic Lipase Inhibitors.

Project description:Obesity contributes to the genesis of many metabolic disorders including dyslipidemia, coronary heart disease (CHD), nonalcoholic fatty liver, type 2 diabetes, etc. Pancreatic lipase plays a vital role in food fat digestion and absorption. Therefore, to control obesity, inhibition of pancreatic lipase is the active therapy. Thus, novel natural product derived labdane appended triazoles with pancreatic lipase inhibition potential were designed and synthesized. Among these hybrids, 6b and 6f exhibited excellent inhibitory activity (IC50 0.75 ± 0.02 ?M and 0.77 ± 0.01 ?M), slightly better than that of the positive control Orlistat (IC50 0.8 ± 0.03 ?M). Compounds 6c, 6e, and 6g-j inhibited the PL comparable to that of positive control. Interestingly none of the compounds showed cytotoxicity (Hep G2) in the concentration range from 0.5 to 100 ?M. Overall results reveal the potential of labdane appended triazoles as antiobesity agents.

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A landmark in drug discovery based on complex natural product synthesis.

Project description:Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.

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Chromatographic editing enhances natural product discovery.

Project description:Fungi are known for their diverse biologically active secondary metabolites, compounds that have provided the basis for many landmark therapeutics in the last century. Due to ease of collection and culturing, the existing fungal chemical literature is vast, and fungal natural product isolation can often be hindered by the numerous nuisance and pan-toxic compounds that many strains produce. Dereplication efforts, aimed at identifying such compounds early in the purification, are imperative to reduce time and expense of rediscovery of known metabolites. The common practice of dereplication then deprioritizes samples containing nuisance compounds and often excludes them from the drug discovery workflow. We have implemented a two-step dereplication protocol that uses tandem mass spectrometry to identify nuisance compounds, followed by mass-directed chromatographic editing to remove them while leaving the remaining 'edited extract' in the drug discovery workflow. This two-step strategy facilitates rapid and more accurate evaluation of the chemical potential of high-throughput extract screening campaigns by consideration of bioactivity beyond that triggered by known metabolites. We demonstrate the isolation of a new natural product antibiotic from an otherwise toxic extract using the technique.

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Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening.

Project description:Cholesterol plays an important role in living cells. However, a very high level of cholesterol may lead to atherosclerosis. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase is the key enzyme in the cholesterol biosynthesis pathway, and the statin-like drugs are inhibitors of human HMG-CoA reductase (hHMGR). The present study aimed to virtually screen for potential hHMGR inhibitors from natural product to discover hypolipidemic drug candidates with fewer side effects and lesser toxicities. We used the 3D structure 1HWK from the PDB (Protein Data Bank) database of hHMGR as the target to screen for the strongly bound compounds from the traditional Chinese medicine database. Many interesting molecules including polyphenolic compounds, polisubstituted heterocyclics, and linear lipophilic alcohols were identified and their ADMET (absorption, disrtibution, metabolism, excretion, toxicity) properties were predicted. Finally, four compounds were obtained for the in vitro validation experiments. The results indicated that curcumin and salvianolic acid C can effectively inhibit hHMGR, with IC50 (half maximal inhibitory concentration) values of 4.3 µM and 8 µM, respectively. The present study also demonstrated the feasibility of discovering new drug candidates through structure-based virtual screening.

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