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      Medicinal polypharmacology—a scientific glossary of terminology and concepts

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          Abstract

          Medicinal polypharmacology is one answer to the complex reality of multifactorial human diseases that are often unresponsive to single-targeted treatment. It is an admittance that intrinsic feedback mechanisms, crosstalk, and disease networks necessitate drugs with broad modes-of-action and multitarget affinities. Medicinal polypharmacology grew to be an independent research field within the last two decades and stretches from basic drug development to clinical research. It has developed its own terminology embedded in general terms of pharmaceutical drug discovery and development at the intersection of medicinal chemistry, chemical biology, and clinical pharmacology. A clear and precise language of critical terms and a thorough understanding of underlying concepts is imperative; however, no comprehensive work exists to this date that could support researchers in this and adjacent research fields. In order to explore novel options, establish interdisciplinary collaborations, and generate high-quality research outputs, the present work provides a first-in-field glossary to clarify the numerous terms that have originated from various individual disciplines.

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          Most cited references94

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          Network pharmacology: the next paradigm in drug discovery.

          The dominant paradigm in drug discovery is the concept of designing maximally selective ligands to act on individual drug targets. However, many effective drugs act via modulation of multiple proteins rather than single targets. Advances in systems biology are revealing a phenotypic robustness and a network structure that strongly suggests that exquisitely selective compounds, compared with multitarget drugs, may exhibit lower than desired clinical efficacy. This new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development--efficacy and toxicity. Integrating network biology and polypharmacology holds the promise of expanding the current opportunity space for druggable targets. However, the rational design of polypharmacology faces considerable challenges in the need for new methods to validate target combinations and optimize multiple structure-activity relationships while maintaining drug-like properties. Advances in these areas are creating the foundation of the next paradigm in drug discovery: network pharmacology.
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            Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.

            Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP > 4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.
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              Network biology: understanding the cell's functional organization.

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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/1393578/overviewRole: Role: Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/776785/overviewRole: Role: Role: Role: Role: Role:
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                18 July 2024
                2024
                : 15
                : 1419110
                Affiliations
                [1] 1 Medicinal Chemistry and Systems Polypharmacology , Medical Systems Biology Division , Lübeck Institute of Experimental Dermatology (LIED) , University of Lübeck and University Medical Center Schleswig-Holstein (UKSH) , Lübeck, Germany
                [2] 2 Department of Biopharmacy , Medical University of Lublin , Lublin, Poland
                [3] 3 Institute of Clinical Pharmacology , University Medical Center Göttingen , Göttingen, Germany
                [4] 4 Department of Medical Education , Augsburg University Medicine , Augsburg, Germany
                Author notes

                Edited by: Yuxiang Dong, University of Nebraska Medical Center, United States

                Reviewed by: Elena Puris, Heidelberg University, Germany

                [ † ]

                These authors have contributed equally to this work

                Article
                1419110
                10.3389/fphar.2024.1419110
                11292611
                39092220
                6360b5e3-e6b4-4b30-bf6a-c050b66f5118
                Copyright © 2024 Stefan and Rafehi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 17 April 2024
                : 30 April 2024
                Funding
                Funded by: Deutsche Forschungsgemeinschaft , doi 10.13039/501100001659;
                The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. SS was supported by the Research Grant program of the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG, Germany; #504079349 [PANABC]). MR received funding from the DFG (#437446827) and the research program of the University Medical Center Göttingen.
                Categories
                Pharmacology
                Mini Review
                Custom metadata
                Experimental Pharmacology and Drug Discovery

                Pharmacology & Pharmaceutical medicine
                polypharmacolome,drug repurposing,target repurposing,privileged structures,privileged ligands,network pharmacology,chemogenomic space,superfolds

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