The Experts below are selected from a list of 1584 Experts worldwide ranked by ideXlab platform
Andrea Cavalli - One of the best experts on this subject based on the ideXlab platform.
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multitarget drug discovery and Polypharmacology
ChemMedChem, 2016Co-Authors: Maria Laura Bolognesi, Andrea CavalliAbstract:Promising promiscuity: Guest editors Maria Laura Bolognesi and Andrea Cavalli set the stage for this ChemMedChem Special Issue on Polypharmacology and Multitarget Drugs. They highlight cases in which a departure from the "one target, one drug" paradigm has proven advantageous, with single molecules that can engage two or more targets to address a given pathology. Articles in this issue underscore the importance of focusing ever more attention to Polypharmacology in drug discovery efforts.
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the role of fragment based and computational methods in Polypharmacology
Drug Discovery Today, 2012Co-Authors: Giovanni Bottegoni, Andrea Cavalli, Angelo D Favia, Maurizio RecanatiniAbstract:Polypharmacology-based strategies are gaining increased attention as a novel approach to obtaining potentially innovative medicines for multifactorial diseases. However, some within the pharmaceutical community have resisted these strategies because they can be resource-hungry in the early stages of the drug discovery process. Here, we report on fragment-based and computational methods that might accelerate and optimize the discovery of multitarget drugs. In particular, we illustrate that fragment-based approaches can be particularly suited for Polypharmacology, owing to the inherent promiscuous nature of fragments. In parallel, we explain how computer-assisted protocols can provide invaluable insights into how to unveil compounds theoretically able to bind to more than one protein. Furthermore, several pragmatic aspects related to the use of these approaches are covered, thus offering the reader practical insights on multitarget-oriented drug discovery projects.
Yao Peng - One of the best experts on this subject based on the ideXlab platform.
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5 ht2c receptor structures reveal the structural basis of gpcr Polypharmacology
Cell, 2018Co-Authors: Yao Peng, John D Mccorvy, K Harpsoe, Katherine Lansu, Shuguang Yuan, Petr Popov, Tao CheAbstract:Summary Drugs frequently require interactions with multiple targets—via a process known as Polypharmacology—to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT 2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT 2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT 2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT 2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 A and 2.7 A, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of Polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.
Maria Laura Bolognesi - One of the best experts on this subject based on the ideXlab platform.
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from combinations to multitarget directed ligands a continuum in alzheimer s disease Polypharmacology
Medicinal Research Reviews, 2021Co-Authors: Claudia Albertini, Alessandra Salerno, Pedro De Sena Murteira Pinheiro, Maria Laura BolognesiAbstract:The continued drug discovery failures in complex neurodegenerative diseases, including Alzheimer's disease (AD), has raised questions about the classical paradigm "one-drug, one-target, one-disease." In parallel, the ever-increasing awareness of the multiplicity of the underlying pathways has led to the affirmation of polypharmacological approaches. Polypharmacology, which broadly embodies the use of pharmaceutical agents acting on multiple targets, seems to be the best way to restore the complex diseased network and to provide disease-modifying effects in AD. In this review, our aim is to provide a roadmap into a world that is still only partly explored and that should be seen as a continuum of pharmacological opportunities, from drug combinations to multitarget-directed ligands (both codrugs and hybrids). Each modality has unique features that can be effectively exploited by medicinal chemists. We argue that understanding their advantages and drawbacks is very helpful in choosing a proper approach and developing successful AD multitarget drug-discovery endeavors. We also briefly dwell on (co)target validation, an aspect that is quite often neglected, but critical for an efficient clinical translation. We substantiate our discussion with instructive examples taken from the recent literature. Our wish is that, in spite of the specter of the high attrition rates, best researchers preferring to enter, stay, and progress in the field would help grow the sector and develop AD Polypharmacology to full potential.
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from combinations to single molecule Polypharmacology cromolyn ibuprofen conjugates for alzheimer s disease
Molecules, 2021Co-Authors: Claudia Albertini, Marina Naldi, Sabrina Petralla, Silvia Strocchi, Daniela Grifoni, Barbara Monti, Manuela Bartolini, Maria Laura BolognesiAbstract:Despite Alzheimer's disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm "one target-one drug-one disease" in delivering effective medications for AD, Polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn-ibuprofen drug combination into single-molecule "codrugs." Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn-ibuprofen conjugates (4-6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aβ42-amyloid self-aggregation, and their cellular neuroprotective effect against Aβ42-induced neurotoxicity. The fact that 6 effectively reduced Aβ-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aβ42-expressing Drosophila and to improve fly locomotor performance.
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harnessing Polypharmacology with medicinal chemistry
ACS Medicinal Chemistry Letters, 2019Co-Authors: Maria Laura BolognesiAbstract:Polypharmacology has expanded enormously over the last ten years, with several multitarget drugs (MTDs) already in the market. This Viewpoint provides a basis for a discussion about the critical need to develop MTDs in a more rationale and conscious way. A checklist to maximize success in Polypharmacology is proposed.
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multitarget drug discovery and Polypharmacology
ChemMedChem, 2016Co-Authors: Maria Laura Bolognesi, Andrea CavalliAbstract:Promising promiscuity: Guest editors Maria Laura Bolognesi and Andrea Cavalli set the stage for this ChemMedChem Special Issue on Polypharmacology and Multitarget Drugs. They highlight cases in which a departure from the "one target, one drug" paradigm has proven advantageous, with single molecules that can engage two or more targets to address a given pathology. Articles in this issue underscore the importance of focusing ever more attention to Polypharmacology in drug discovery efforts.
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Polypharmacology in a single drug multitarget drugs
Current Medicinal Chemistry, 2013Co-Authors: Maria Laura BolognesiAbstract:Polypharmacology offers a model for the way drug discovery must evolve to develop therapies most suited to treating currently incurable diseases. It is driven by a worldwide demand for safer, more effective, and affordable medicines against the most complex diseases, and by the failures of modern drug discovery to provide these. Polypharmacology can involve combinations and/or multitarget drugs (MTD). Although not mutually exclusive, my premise is that MTDs have inherent advantages over combinations. This review article focuses on MTDs from a medicinal chemistry perspective. I will explore their use in current clinical practice, their likely application in the future, and the challenges to be overcome to achieve this goal.
Jordi Mestres - One of the best experts on this subject based on the ideXlab platform.
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Polypharmacology in precision oncology current applications and future prospects
Current Pharmaceutical Design, 2017Co-Authors: Albert A Antolin, Paul Workman, Jordi Mestres, Bissan AllazikaniAbstract:Over the past decade, a more comprehensive, large-scale approach to studying cancer genetics and biology has revealed the challenges of tumor heterogeneity, adaption, evolution and drug resistance, while systems-based pharmacology and chemical biology strategies have uncovered a much more complex interaction between drugs and the human proteome than was previously anticipated. In this mini-review we assess the progress and potential of drug Polypharmacology in biomarker-driven precision oncology. Polypharmacology not only provides great opportunities for drug repurposing to exploit off-target effects in a new single-target indication but through simultaneous blockade of multiple targets or pathways offers exciting opportunities to slow, overcome or even prevent inherent or adaptive drug resistance. We highlight the many challenges associated with exploiting known or desired Polypharmacology in drug design and development, and assess computational and experimental methods to uncover unknown Polypharmacology. A comprehensive understanding of the intricate links between Polypharmacology, efficacy and safety is urgently needed if we are to tackle the enduring challenge of cancer drug resistance and to fully exploit Polypharmacology for the ultimate benefit of cancer patients.
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distant Polypharmacology among mlp chemical probes
ACS Chemical Biology, 2015Co-Authors: Albert A Antolin, Jordi MestresAbstract:Small molecules are essential tool compounds to probe the role of proteins in biology and advance toward more efficient therapeutics. However, they are used without a complete knowledge of their selectivity across the entire proteome, at risk of confounding their effects due to unknown off-target interactions. Current state-of-the-art computational approaches to predicting the affinity profile of small molecules offer a means to anticipate potential nonobvious selectivity liabilities of chemical probes. The application of in silico target profiling on the full set of chemical probes from the NIH Molecular Libraries Program (MLP) resulted in the identification of biologically relevant in vitro affinities for proteins distantly related to the primary targets of ML006, ML123, ML141, and ML204, helping to lower the risk of their further use in chemical biology.
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identification of similar binding sites to detect distant Polypharmacology
Molecular Informatics, 2013Co-Authors: Xavier Jalencas, Jordi MestresAbstract:The ability of small molecules to interact with multiple proteins is referred to as Polypharmacology. This property is often linked to the therapeutic action of drugs but it is known also to be responsible for many of their side effects. Because of its importance, the development of computational methods that can predict drug Polypharmacology has become an important line of research that led recently to the identification of many novel targets for known drugs. Nowadays, the majority of these methods are based on measuring the similarity of a query molecule against the hundreds of thousands of molecules for which pharmacological data on thousands of proteins are available in public sources. However, similarity-based methods are inherently biased by the chemical coverage offered by the active molecules present in those public repositories, which limits significantly their capacity to predict interactions with proteins structurally and functionally unrelated to any of the already known targets for drugs. It is in this respect that structure-based methods aiming at identifying similar binding sites may offer an alternative complementary means to ligand-based methods for detecting distant Polypharmacology. The different existing approaches to binding site detection, representation, comparison, and fragmentation are reviewed and recent successful applications presented.
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on the origins of drug Polypharmacology
MedChemComm, 2013Co-Authors: Xavier Jalencas, Jordi MestresAbstract:The ability of small molecules to interact with multiple proteins is commonly referred to as Polypharmacology. The now widely accepted Polypharmacology of drugs is of particular interest for human health as it has implications beyond therapeutic efficacy, from anticipating adverse drug reactions to identifying potential repurposing opportunities. There have been a number of studies relating the extent of drug Polypharmacology to the physicochemical properties and fragment composition of the drug itself, but also to the protein family and distant binding site similarities of the drug's primary target. Taken together, all these observations lead to speculate that the origins of drug Polypharmacology may lie at the heart of protein evolution and that Polypharmacology may just be a reminiscent signature of some of the mechanisms of adaptation that primitive biological systems developed to increase the chances of survival in a highly variable early chemical environment.
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conciliating binding efficiency and Polypharmacology
Trends in Pharmacological Sciences, 2009Co-Authors: Jordi Mestres, Elisabet GregoripuigjaneAbstract:The association between molecular size and risk of failure has promoted the use of binding efficiency as a prioritization metric in lead selection. Even though by extension it is often referred to as "ligand efficiency", the concept was originally conceived to be strictly applicable to comparing the binding efficiencies of ligands for a single target. With current trends in designing drugs to bind efficiently to multiple targets, a revision of the original binding efficiency definition is carried out. To this aim, the dependency of binding efficiency on Polypharmacology is highlighted in a retrospective analysis of a set of antipsychotic drugs. Statistical standardization of target binding efficiencies relative to basal values obtained from a large background of medicinal chemistry compounds is proposed as a means to conciliate the concepts of binding efficiency and Polypharmacology. Finally, the interplay between binding efficiency and therapeutic efficacy for optimizing natural products, random hits, and fragments is discussed.
Antonio Macchiarulo - One of the best experts on this subject based on the ideXlab platform.
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concepts and molecular aspects in the Polypharmacology of parp 1 inhibitors
ChemMedChem, 2016Co-Authors: Daniela Passeri, Emidio Camaioni, Paride Liscio, Paola Sabbatini, Martina Ferri, Andrea Carotti, Nicola Giacche, Roberto Pellicciari, Antimo Gioiello, Antonio MacchiaruloAbstract:Abstract Recent years have witnessed a renewed interest in PARP-1 inhibitors as promising anticancer agents with multifaceted functions. Particularly exciting developments include the approval of olaparib (Lynparza) for the treatment of refractory ovarian cancer in patients with BRCA1/2 mutations, and the increasing understanding of the Polypharmacology of PARP-1 inhibitors. The aim of this review article is to provide the reader with a comprehensive overview of the distinct levels of the Polypharmacology of PARP-1 inhibitors, including 1) inter-family Polypharmacology, 2) intra-family Polypharmacology, and 3) multi-signaling Polypharmacology. Progress made in gaining insight into the molecular basis of these multiple target-independent and target-dependent activities of PARP-1 inhibitors are discussed, with an outlook on the potential impact that a better understanding of Polypharmacology may have in aiding the explanation as to why some drug candidates work better than others in clinical settings, albeit acting on the same target with similar inhibitory potency.
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from Polypharmacology to target specificity the case of parp inhibitors
Current Topics in Medicinal Chemistry, 2013Co-Authors: Paride Liscio, Emidio Camaioni, Andrea Carotti, Roberto Pellicciari, Antonio MacchiaruloAbstract:Poly(ADP-ribose)polymerases (PARPs) catalyze a post-transcriptional modification of proteins, consisting in the attachment of mono, oligo or poly ADP-ribose units from NAD+ to specific polar residues of target proteins. The scientific interest in members of this superfamily of enzymes is continuously growing since they have been implicated in a range of diseases including stroke, cardiac ischemia, cancer, inflammation and diabetes. Despite some inhibitors of PARP-1, the founder member of the superfamily, have advanced in clinical trials for cancer therapy, and other members of PARPs have recently been proposed as interesting drug targets, challenges exist in understanding the Polypharmacology of current PARP inhibitors as well as developing highly selective chemical tools to unravel specific functions of each member of the superfamily. Beginning with an overview on the molecular aspects that affect Polypharmacology, in this article we discuss how these may have an impact on PARP research and drug discovery. Then, we review the most selective PARP inhibitors hitherto reported in literature, giving an update on the molecular aspects at the basis of selective PARP inhibitor design. Finally, some outlooks on current issues and future directions in this field of research are also provided.
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PARP inhibitors: Polypharmacology versus selective inhibition
FEBS Journal, 2013Co-Authors: Tobias Ekblad, Herwig Schüler, Emidio Camaioni, Antonio MacchiaruloAbstract:Inhibition of ADP-ribosyltransferases with diphtheria toxin homology (ARTD), widely known as the poly(ADP-ribose) polymerase (PARP) family, is a strategy under development for treatment of various conditions, including cancers and ischemia. Here, we give a brief summary of ARTD enzyme functions and the implications for their potential as therapeutic targets. We present an overview of the PARP inhibitors that have been used in clinical trials. Finally, we summarize recent insights from structural biology, and discuss the molecular aspects of PARP inhibitors in terms of broad-range versus selective inhibition of ARTD family enzymes.
