Target identification of natural and traditional medicines with quantitative chemical proteomics approaches

Wang, Jigang; Gao, Liqian; Lee, Yew Mun; Kalesh, Karunakaran A.; Ong, Yong Siang; Lim, Joseph J.; Jee, Joo‐Eun; Sun, Hongyan; Lee, Su Seong; Hua, Zichun; Lin, Qingsong

doi:10.1016/j.pharmthera.2016.01.010

Cited by 103 publications

(80 citation statements)

References 78 publications

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“…The druggable target identification is extremely important for seeking therapy drugs (25)(26)(27). To explore the direct cell target of SA (28), we designed a small-molecular probe based on SA structure and found it selectively targets IMPDH2, but not IMPDH1.…”

Section: Discussionmentioning

confidence: 99%

Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy

Liao

Song

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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Inosine monophosphate dehydrogenase (IMPDH) of human is an attractive target for immunosuppressive agents. Currently, smallmolecule inhibitors do not show good selectivity for different IMPDH isoforms (IMPDH1 and IMPDH2), resulting in some adverse effects, which limit their use. Herein, we used a small-molecule probe specifically targeting IMPDH2 and identified Cysteine residue 140 (Cys140) as a selective druggable site. On covalently binding to Cys140, the probe exerts an allosteric regulation to block the catalytic pocket of IMPDH2 and further induces IMPDH2 inactivation, leading to an effective suppression of neuroinflammatory responses. However, the probe does not covalently bind to IMPDH1. Taken together, our study shows Cys140 as a druggable site for selectively inhibiting IMPDH2, which provides great potential for development of therapy agents for autoimmune and neuroinflammatory diseases with less unfavorable tolerability profile.nosine monophosphate dehydrogenase (IMPDH) is a major rate-limiting enzyme involved in guanosine and deoxyguanosine biosynthesis and widely expressed in immunocytes (1). There exist two IMPDH isoforms (IMPDH1 and IMPDH2), which are encoded by distinct genes (2, 3). Many inflammation-relevant diseases have been specially characterized by the high expression of isoform II of IMPDH (IMPDH2) in rapidly proliferating immunocytes, rather than the "housekeeping" type I isoform (IMPDH1) in normal human leukocytes and lymphocytes (4, 5). Therefore, selective targeting of IMPDH2 with small molecules is an attractive topic for development of antiinflammation agents with low side effects.Both IMPDH isoforms contain two major domains: the catalytic domain for substrate interaction and the Bateman domain, which is not required for catalytic activity but exerts an important allosteric regulation effect on IMPDH activity by communicating with the catalytic domain (6, 7). By influencing catalytic domain activity, the Bateman domain can regulate IMPDH function and further blocks the downstream-of-inflammation signaling pathways (8, 9). Currently, IMPDH inhibitors are divided into two major categories. One kind of inhibitor, including 6-chloropurine riboside ribavirin and mizoribine, targets the binding pocket of the natural substrate, inosine monophosphate (IMP). Another kind of inhibitor (e.g., mycophenolic acid and thiazole-4-carboxamide adenine dinucleotide) targets the site of the cofactor, NAD + / NADH, which usually leads to low selectivity or even side effects in clinical trials, such as diarrhea and leukopenia (10, 11). Moreover, a third ligand has been speculated to bind to a possible site far from the IMP and NAD + pockets as an allosteric inhibitor. However, an allosteric site for designing selective IMPDH2 inhibitors has been largely unexplored.Natural small molecules remain promising drug sources (12, 13). In the present study, we report that a natural small-molecule probe, sappanone A (SA, Fig.1A), demonstrated significant inhibitory effects on neuroinflammation by directly targetin...

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Section: Discussionmentioning

confidence: 99%

Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy

Liao

Song

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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“…Here, we employed DIA‐based proteomics to dissect the protein alteration involved in the molecular mechanisms of OA regulation (Figure ). Proteomics approaches play an important role in exploring drug targets and mechanisms of action for active ingredients from TCMs . Our GO and IPA analyses suggested that OA regulated apoptosis and cell cycle arrest, with p53/ROS pathway as central events.…”

Section: Discussionmentioning

confidence: 88%

Proteomic Analysis Reveals that Odoroside A Triggers G2/M Arrest and Apoptosis in Colorectal Carcinoma Through ROS‐p53 Pathway

et al. 2019

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Odoroside A (OA) is an active ingredient extracted from the leaves of Nerium oleander Linn. (Apocynaceae). This study aims to examine the anticancer bioactivity of OA against CRC cells and to investigate the action mechanisms involved. As a result, OA can significantly inhibit cellular ability and induce apoptosis of CRC cells in a concentration‐dependent manner without any obvious cytotoxicity in normal colorectal epithelial cells. Then, quantitative proteomics combined with bioinformatics is adopted to investigate the alterations of proteins and signaling pathways in response to OA treatment. As suggested by the proteomic analysis, flow cytometry and Western blotting analyses validate that exposure of CRC cells to OA causes cell cycle arrest and apoptosis, accompanied with the activation of the ROS/p53 signaling pathway. This observation demonstrates that OA, as a natural product, can induce oxidative stress to suppress tumor cell growth, implicating a novel therapeutic agent against CRC without obvious side effects.

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“…Recent advances in chemical proteomics have lowered the barriers to target identification . Chemical proteomics combines affinity chromatography approaches and mass spectrometry in order to systematically identify compound interactions with target proteins . A number of quantitative proteomics approaches have been suggested, such as metabolic labeling or chemical labeling .…”

Section: Target and Mechanism Identification Methodsmentioning

confidence: 99%

Application of Combination High‐Throughput Phenotypic Screening and Target Identification Methods for the Discovery of Natural Product‐Based Combination Drugs

Isgut

Mukkavilli

Yang

et al. 2017

Medicinal Research Reviews

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Modern drug discovery efforts have had mediocre success rates with increasing developmental costs, and this has encouraged pharmaceutical scientists to seek innovative approaches. Recently with the rise of the fields of systems biology and metabolomics, network pharmacology (NP) has begun to emerge as a new paradigm in drug discovery, with a focus on multiple targets and drug combinations for treating disease. Studies on the benefits of drug combinations lay the groundwork for a renewed focus on natural products in drug discovery. Natural products consist of a multitude of constituents that can act on a variety of targets in the body to induce pharmacodynamic responses that may together culminate in an additive or synergistic therapeutic effect. Although natural products cannot be patented, they can be used as starting points in the discovery of potent combination therapeutics. The optimal mix of bioactive ingredients in natural products can be determined via phenotypic screening. The targets and molecular mechanisms of action of these active ingredients can then be determined using chemical proteomics, and by implementing a reverse pharmacokinetics approach. This review article provides evidence supporting the potential benefits of natural product-based combination drugs, and summarizes drug discovery methods that can be applied to this class of drugs.

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Target identification of natural and traditional medicines with quantitative chemical proteomics approaches

Cited by 103 publications

References 78 publications

Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy

Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy

Proteomic Analysis Reveals that Odoroside A Triggers G2/M Arrest and Apoptosis in Colorectal Carcinoma Through ROS‐p53 Pathway

Application of Combination High‐Throughput Phenotypic Screening and Target Identification Methods for the Discovery of Natural Product‐Based Combination Drugs

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