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SLAS Discovery : Advancing Life... Apr 2024Covalent hits for drug discovery campaigns are neither fantastic beasts nor mythical creatures, they can be routinely identified through electrophile-first screening... (Review)
Review
Covalent hits for drug discovery campaigns are neither fantastic beasts nor mythical creatures, they can be routinely identified through electrophile-first screening campaigns using a suite of different techniques. These include biophysical and biochemical methods, cellular approaches, and DNA-encoded libraries. Employing best practice, however, is critical to success. The purpose of this review is to look at state of the art covalent hit identification, how to identify hits from a covalent library and how to select compounds for medicinal chemistry programmes.
Topics: Drug Discovery; Humans; Small Molecule Libraries; Chemistry, Pharmaceutical; High-Throughput Screening Assays
PubMed: 38278484
DOI: 10.1016/j.slasd.2024.01.003 -
Annual Review of Pharmacology and... Jan 2024Interindividual variability in genes encoding drug-metabolizing enzymes, transporters, receptors, and human leukocyte antigens has a major impact on a patient's response... (Review)
Review
Interindividual variability in genes encoding drug-metabolizing enzymes, transporters, receptors, and human leukocyte antigens has a major impact on a patient's response to drugs with regard to efficacy and safety. Enabled by both technological and conceptual advances, the field of pharmacogenomics is developing rapidly. Major progress in omics profiling methods has enabled novel genotypic and phenotypic characterization of patients and biobanks. These developments are paralleled by advances in machine learning, which have allowed us to parse the immense wealth of data and establish novel genetic markers and polygenic models for drug selection and dosing. Pharmacogenomics has recently become more widespread in clinical practice to personalize treatment and to develop new drugs tailored to specific patient populations. In this review, we provide an overview of the latest developments in the field and discuss the way forward, including how to address the missing heritability, develop novel polygenic models, and further improve the clinical implementation of pharmacogenomics.
Topics: Humans; Pharmacogenetics; Membrane Transport Proteins; Technology
PubMed: 37506333
DOI: 10.1146/annurev-pharmtox-051921-091209 -
British Journal of Pharmacology Oct 2023The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format,...
The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16182. Transporters are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Topics: Humans; Databases, Pharmaceutical; Ligands; Ion Channels; Receptors, G-Protein-Coupled; Receptors, Cytoplasmic and Nuclear; Pharmacology
PubMed: 38123156
DOI: 10.1111/bph.16182 -
European Journal of Medicinal Chemistry Nov 2023Nod-like receptor protein 3 (NLRP3), a therapeutic target that has a close relationship with inflammatory diseases, has drawn significant attention from researchers in... (Review)
Review
Nod-like receptor protein 3 (NLRP3), a therapeutic target that has a close relationship with inflammatory diseases, has drawn significant attention from researchers in the field. An increasing number of NLRP3 inhibitors have been reported since NLRP3 was identified as a biomarker and inflammatory therapeutic target. Inhibiting NLRP3 has been widely studied as therapeutics for the treatment of cryopyrin associated periodic syndrome (CAPS), inflammatory bowel disease (IBD), nonalcoholic steatohepatitis (NASH), arthrolithiasis, Alzheimer's disease (AD) and Parkinson's disease (PD). This review updates the recently reported (2019 to mid-2023) molecule inhibitors targeting the NLRP3 inflammasome pathway, summarizes their structure-activity relationships (SARs), and discusses the therapeutic effects on inflammatory diseases. I hope this review will contribute to the development of novel inhibitors targeting NLRP3 inflammasome pathway as potential drugs.
Topics: Humans; Chemistry, Pharmaceutical; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Alzheimer Disease; NLR Proteins
PubMed: 37639823
DOI: 10.1016/j.ejmech.2023.115750 -
Clinical Pharmacology and Therapeutics Mar 2024
Topics: Humans; Biological Products; Pharmacology, Clinical; Drug Development
PubMed: 38363287
DOI: 10.1002/cpt.3179 -
Angewandte Chemie (International Ed. in... Jul 2023Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into... (Review)
Review
Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into the structure of biologically active small molecules to allow for the optical control of their potency. Going beyond trial and error, photopharmacology has progressively applied rational drug design methodologies to devise light-controlled bioactive ligands. In this review, we categorize photopharmacological efforts from the standpoint of medicinal chemistry strategies, focusing on diffusible photochromic ligands modified with photoswitches that operate through E-Z bond isomerization. In the vast majority of cases, photoswitchable ligands are designed as analogs of existing compounds, through a variety of approaches. By analyzing in detail a comprehensive list of instructive examples, we describe the state of the art and discuss future opportunities for rational design in photopharmacology.
Topics: Ligands; Drug Design; Chemistry, Pharmaceutical
PubMed: 37026576
DOI: 10.1002/anie.202300681 -
Journal of Clinical Oncology : Official... Aug 2023
Topics: Humans; Pharmacogenomic Testing; Informed Consent; Pharmacogenetics; Genetic Testing
PubMed: 37267582
DOI: 10.1200/JCO.23.00664 -
International Journal of Molecular... Nov 2023The Hawaiian Islands are renowned for their exceptional biodiversity and are host to a plethora of endemic plant species, which have been utilized in traditional... (Review)
Review
The Hawaiian Islands are renowned for their exceptional biodiversity and are host to a plethora of endemic plant species, which have been utilized in traditional Hawaiian medicine. This scientific review provides an in-depth analysis of the phytochemistry and biological studies of selected endemic Hawaiian plants, highlighting their medicinal properties and therapeutic potential. A literature search was conducted, utilizing major academic databases such as SciFinder, Scopus, Web of Science, PubMed, Google Scholar, Science Direct, and the Scientific Information Database. The primary objective of this search was to identify relevant scholarly articles pertaining to the topic of the review, which focused on the phytochemistry and biological studies of endemic Hawaiian plants. Utilizing these databases, a comprehensive range of literature was obtained, facilitating a comprehensive examination of the subject matter. This review emphasizes the rich phytochemical diversity and biological activities found in Endemic Hawaiian plants, showcasing their potential as sources of novel therapeutic agents. Given the unique biodiversity of Hawaii and the cultural significance of these plants, continued scientific exploration, conservation, and sustainable utilization of these valuable resources is necessary to unlock the full potential of these plant species in drug discovery and natural product-based therapeutics.
Topics: Plants, Medicinal; Ethnopharmacology; Phytotherapy; Plant Extracts; Hawaii; Phytochemicals
PubMed: 38003513
DOI: 10.3390/ijms242216323 -
Molecules (Basel, Switzerland) Aug 2023Herbal medicines have gained recognition among physicians and patients due to their lower adverse effects compared to modern medicines. They are extensively used to... (Review)
Review
Herbal medicines have gained recognition among physicians and patients due to their lower adverse effects compared to modern medicines. They are extensively used to treat various diseases, including cancer, cardiovascular issues, chronic inflammation, microbial contamination, diabetes, obesity, and hepatic disorders, among others. Unfortunately, the clinical application of herbal medicines is limited by their low solubility and inadequate bioavailability. Utilizing herbal medicines in the form of nanocrystals (herbal medicine nanocrystals) has shown potential in enhancing solubility and bioavailability by reducing the particle size, increasing the specific surface area, and modifying the absorption mechanisms. Multiple studies have demonstrated that these nanocrystals significantly improve drug efficacy by reducing toxicity and increasing bioavailability. This review comprehensively examines therapeutic approaches based on herbal medicine nanocrystals. It covers the preparation principles, key factors influencing nucleation and polymorphism control, applications, and limitations. The review underscores the importance of optimizing delivery systems for successful herbal medicine nanocrystal therapeutics. Furthermore, it discusses the main challenges and opportunities in developing herbal medicine nanocrystals for the purpose of treating conditions such as cancer, inflammatory diseases, cardiovascular disorders, mental and nervous diseases, and antimicrobial infections. In conclusion, we have deliberated regarding the hurdles and forthcoming outlook in the realm of nanotoxicity, in vivo kinetics, herbal ingredients as stabilizers of nanocrystals, and the potential for surmounting drug resistance through the utilization of nanocrystalline formulations in herbal medicine. We anticipate that this review will offer innovative insights into the development of herbal medicine nanocrystals as a promising and novel therapeutic strategy.
Topics: Humans; Herbal Medicine; Plants, Medicinal; Biological Availability; Nanoparticles; Plant Extracts
PubMed: 37687199
DOI: 10.3390/molecules28176370 -
Genes Jan 2024The flavoenzyme N-ribosyldihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2) catalyzes two-electron reductions of quinones. NQO2 contributes to the metabolism of... (Review)
Review
The flavoenzyme N-ribosyldihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2) catalyzes two-electron reductions of quinones. NQO2 contributes to the metabolism of biogenic and xenobiotic quinones, including a wide range of antitumor drugs, with both toxifying and detoxifying functions. Moreover, NQO2 activity can be inhibited by several compounds, including drugs and phytochemicals such as flavonoids. NQO2 may play important roles that go beyond quinone metabolism and include the regulation of oxidative stress, inflammation, and autophagy, with implications in carcinogenesis and neurodegeneration. is a highly polymorphic gene with several allelic variants, including insertions (I), deletions (D) and single-nucleotide (SNP) polymorphisms located mainly in the promoter, but also in other regulatory regions and exons. This is the first systematic review of the literature reporting on NQO2 gene variants as risk factors in degenerative diseases or drug adverse effects. In particular, hypomorphic 29 bp I alleles have been linked to breast and other solid cancer susceptibility as well as to interindividual variability in response to chemotherapy. On the other hand, hypermorphic polymorphisms were associated with Parkinson's and Alzheimer's disease. The I and D promoter variants and other NQO2 polymorphisms may impact cognitive decline, alcoholism and toxicity of several nervous system drugs. Future studies are required to fill several gaps in NQO2 research.
Topics: Benzoquinones; Oxidoreductases; Pharmacogenetics; Quinone Reductases; Humans
PubMed: 38254976
DOI: 10.3390/genes15010087