Curcumin is a constituent (up to ∼5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compounds) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No double-blinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead. On the basis of this in-depth evaluation, potential new directions for research on curcuminoids are discussed.

The Essential Medicinal Chemistry of Curcumin

Naivety about promiscuous, assay-duping molecules is polluting the literature and wasting resources, warn Jonathan Baell and Michael A. Walters.

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Chemistry: Chemical con artists foil drug discovery

Simulations Complement Experimental Studies Jessica Nasica-Labouze,† Phuong H. Nguyen,† Fabio Sterpone,† Olivia Berthoumieu,‡ Nicolae-Viorel Buchete, Sebastien Cote, Alfonso De Simone, Andrew J. Doig, Peter Faller,‡ Angel Garcia, Alessandro Laio, Mai Suan Li, Simone Melchionna, Normand Mousseau, Yuguang Mu, Anant Paravastu, Samuela Pasquali,† David J. Rosenman, Birgit Strodel, Bogdan Tarus,† John H. Viles, Tong Zhang,†,▲ Chunyu Wang, and Philippe Derreumaux*,†,□ †Laboratoire de Biochimie Theorique, Institut de Biologie Physico-Chimique (IBPC), UPR9080 CNRS, Universite Paris Diderot, Sorbonne Paris Cite, 13 rue Pierre et Marie Curie, 75005 Paris, France ‡LCC (Laboratoire de Chimie de Coordination), CNRS, Universite de Toulouse, Universite Paul Sabatier (UPS), Institut National Polytechnique de Toulouse (INPT), 205 route de Narbonne, BP 44099, Toulouse F-31077 Cedex 4, France School of Physics & Complex and Adaptive Systems Laboratory, University College Dublin, Belfield, Dublin 4, Ireland Deṕartement de Physique and Groupe de recherche sur les proteines membranaires (GEPROM), Universite de Montreal, C.P. 6128, succursale Centre-ville, Montreal, Quebec H3C 3T5, Canada Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom Department of Physics, Applied Physics, & Astronomy, and Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180, United States The International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw, Poland Institute for Computational Science and Technology, SBI Building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam Instituto Processi Chimico-Fisici, CNR-IPCF, Consiglio Nazionale delle Ricerche, 00185 Roma, Italy School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551 Singapore Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University (FAMU-FSU) College of Engineering, 2525 Pottsdamer Street, Tallahassee, Florida 32310, United States National High Magnetic Field Laboratory, 1800 East Paul Dirac Drive, Tallahassee, Florida 32310, United States Institute of Complex Systems: Structural Biochemistry (ICS-6), Forschungszentrum Julich GmbH, 52425 Julich, Germany School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, United Kingdom Institut Universitaire de France, 75005 Paris, France

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Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies

Infections arising from multidrug-resistant pathogenic bacteria are spreading rapidly throughout the world and threaten to become untreatable. The origins of resistance are numerous and complex, but one underlying factor is the capacity of bacteria to rapidly export drugs through the intrinsic activity of efflux pumps. In this Review, we describe recent advances that have increased our understanding of the structures and molecular mechanisms of multidrug efflux pumps in bacteria. Clinical and laboratory data indicate that efflux pumps function not only in the drug extrusion process but also in virulence and the adaptive responses that contribute to antimicrobial resistance during infection. The emerging picture of the structure, function and regulation of efflux pumps suggests opportunities for countering their activities.

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Multidrug efflux pumps: structure, function and regulation

We have previously reported on classes of compounds that can interfere with bioassays via a number of different mechanisms and termed such compounds Pan Assay INterference compoundS, or PAINS. These compounds were defined on the basis of high-throughput data derived from vendor-supplied synthetics. The question therefore arises whether the concept of PAINS is relevant to compounds of natural origin. Here, it is shown that this is indeed the case, but that the context of the biological readout is an important factor that must be brought into consideration.

Feeling Nature's PAINS: Natural Products, Natural Product Drugs, and Pan Assay Interference Compounds (PAINS).

A wide variety of phytochemicals are consumed for their perceived health benefits. Many of these phytochemicals have been found to alter numerous cell functions, but the mechanisms underlying their biological activity tend to be poorly understood. Phenolic phytochemicals are particularly promiscuous modifiers of membrane protein function, suggesting that some of their actions may be due to a common, membrane bilayer-mediated mechanism. To test whether bilayer perturbation may underlie this diversity of actions, we examined five bioactive phenols reported to have medicinal value: capsaicin from chili peppers, curcumin from turmeric, EGCG from green tea, genistein from soybeans, and resveratrol from grapes. We find that each of these widely consumed phytochemicals alters lipid bilayer properties and the function of diverse membrane proteins. Molecular dynamics simulations show that these phytochemicals modify bilayer properties by localizing to the bilayer/solution interface. Bilayer-modifying propensity was verified using a gramicidin-based assay, and indiscriminate modulation of membrane protein function was demonstrated using four proteins: membrane-anchored metalloproteases, mechanosensitive ion channels, and voltage-dependent potassium and sodium channels. Each protein exhibited similar responses to multiple phytochemicals, consistent with a common, bilayer-mediated mechanism. Our results suggest that many effects of amphiphilic phytochemicals are due to cell membrane perturbations, rather than specific protein binding.

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Phytochemicals Perturb Membranes and Promiscuously Alter Protein Function

AcrB is the major multidrug exporter in Escherichia coli. Although several substrate-entrances have been identified, the specificity of these various transport paths remains unclear. Here we present evidence for a substrate channel (channel 3)  from the central cavity of the AcrB trimer, which is connected directly to the deep pocket without first passing the switch-loop and the proximal pocket . Planar aromatic cations, such as ethidium, prefer channel 3 to channels 1 and 2. The efflux through channel 3 increases by targeted mutations and is not in competition with the export of drugs such as minocycline and erythromycin through channels 1 and 2. A switch-loop mutant, in which the pathway from the proximal to the deep pocket is hindered, can export only channel 3-utilizing drugs. The usage of multiple entrances thus contributes to the recognition and transport of a wide range of drugs with different physicochemical properties. Multidrug transporters possess several drug binding sites. Here the authors describe a transport path specific for planar aromatic cations in the E. coli multi-drug transporter AcrB.

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Multiple entry pathways within the efflux transporter AcrB contribute to multidrug recognition

Molecular mechanisms of AcrB-mediated multidrug export.

The rise in multidrug resistance (MDR) is one of the greatest threats to human health worldwide. MDR in bacterial pathogens is a major challenge in healthcare, as bacterial infections are becoming untreatable by commercially available antibiotics. One of the main causes of MDR is the over-expression of intrinsic and acquired multidrug efflux pumps, belonging to the resistance-nodulation-division (RND) superfamily, which can efflux a wide range of structurally different antibiotics. Besides over-expression, however, recent amino acid substitutions within the pumps themselves—causing an increased drug efflux efficiency—are causing additional worry. In this review, we take a closer look at clinically, environmentally and laboratory-evolved Gram-negative bacterial strains and their decreased drug sensitivity as a result of mutations directly in the RND-type pumps themselves (from Escherichia coli, Salmonella enterica, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Acinetobacter baumannii and Legionella pneumophila). We also focus on the evolution of the efflux pumps by comparing hundreds of efflux pumps to determine where conservation is concentrated and where differences in amino acids can shed light on the broad and even broadening drug recognition. Knowledge of conservation, as well as of novel gain-of-function efflux pump mutations, is essential for the development of novel antibiotics and efflux pump inhibitors.

https://www.mdpi.com/2079-6382/10/7/774/pdf

Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time.

Multidrug resistance in Gram-negative bacteria can arise by the over-expression of multidrug efflux pumps, which can extrude a wide range of antibiotics. Here we describe the ancestral Haemophilus influenzae efflux pump AcrB (AcrB-Hi). We performed a phylogenetic analysis of hundreds of RND-type transporters. We found that AcrB-Hi is a relatively ancient efflux pump, which nonetheless can export the same range of antibiotics as its evolved colleague from Escherichia coli. AcrB-Hi was not inhibited by the efflux pump inhibitor ABI-PP, and could export bile salts weakly. This points to an environmental adaptation of RND transporters. We also explain the sensitivity of H. influenzae cells to β-lactams and novobiocin by the outer membrane porin OmpP2. This porin counterbalances the AcrB-Hi efflux by leaking the drugs back into the cells. We hypothesise that multidrug recognition by RND-type pumps is not an evolutionarily acquired ability, and has been present since ancient promiscuous transporters.

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Martijn Zwama

Papers

Phytochemicals Perturb Membranes and Promiscuously Alter Protein Function

Multiple entry pathways within the efflux transporter AcrB contribute to multidrug recognition

Molecular mechanisms of AcrB-mediated multidrug export.

Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time.

Phylogenetic and functional characterisation of the Haemophilus influenzae multidrug efflux pump AcrB.