Polypharmacology: drug discovery for the future. Expert Rev Clin Pharmacol 6(1)

Integrated Molecular Discovery Laboratory, Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA.
Expert Review of Clinical Pharmacology (Impact Factor: 2.18). 01/2013; 6(1):41-7. DOI: 10.1586/ecp.12.74
Source: PubMed


In recent years, even with remarkable scientific advancements and a significant increase of global research and development spending, drugs are frequently withdrawn from markets. This is primarily due to their side effects or toxicities. Drug molecules often interact with multiple targets, coined as polypharmacology, and the unintended drug-target interactions could cause side effects. Polypharmacology remains one of the major challenges in drug development, and it opens novel avenues to rationally design the next generation of more effective, but less toxic, therapeutic agents. This review outlines the latest progress and challenges in polypharmacology studies.

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    • "A large number of small molecular drugs possess multiple targets (polypharmacology), although they were designed to aim at a single target [1]. The " off-target " effect may lead to complicated adverse effects; on the other hands, that may provide an opportunity to repurpose existing drugs [1] [2]. Therefore, it is necessary to profile targets of the small molecule drugs at the proteomic level. "
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    ABSTRACT: A new approach for proteome-wide profiling drug binding proteins by using monolithic capillary affinity chromatography in combination with HPLC-MS/MS is reported. Two immunosuppresive drugs, namely FK506 and cyclosporin A, were utilized as the experimental models for proof-of-concept. The monolithic capillary affinity columns were prepared through a single-step copolymerization of the drug derivatives with glycidyl methacrylate and ethylene dimethacrylate. The capillary chromatography with the affinity monolithic column facilitates the purification of the drug binding proteins from the cell lysate. By combining the capillary affinity column purification and the shot-gun proteomic analysis, totally 33 FK506- and 32 CsA-binding proteins including all the literature reported target proteins of these two drugs were identified. Among them, two proteins, namely voltage-dependent anion-selective channel protein 1 and serine/threonine-protein phosphatase PGAM5 were verified by using the recombinant proteins. The result supports that the monolithic capillary affinity chromatography is likely to become a valuable tool for profiling of binding proteins of small molecular drugs as well as bioactive compounds.
    Journal of Chromatography A 07/2014; 1359. DOI:10.1016/j.chroma.2014.07.020 · 4.17 Impact Factor
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    • "At present, only ∼30 of the ∼350 genes that code for non-olfactory receptors in the human species (2) are truly validated therapeutic targets (3), indicating this family’s immense potential for future drug development. An increasing number of drugs have been found to display polypharmacology, i.e. activity through multiple receptor targets (4). However, endogenous ligands for ∼135 of the so-called orphan receptors have so far eluded researchers. "
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    Nucleic Acids Research 12/2013; 42(Database issue). DOI:10.1093/nar/gkt1255 · 9.11 Impact Factor
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    ABSTRACT: In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed here and the mechanistic portrait of lamellarin D is detailed. Lamellarins frequently serve as a starting point in the design of anticancer compounds. Extensive efforts have been devoted to create novel structures as well as to improve synthetic methods, leading to lamellarins and related pyrrole-derived marine alkaloids.
    Marine Drugs 03/2015; 13(3):1105-1123. DOI:10.3390/md13031105 · 2.85 Impact Factor
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