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Pharmacology Research & Perspectives Dec 2019Paul Ehrlich's concept of the magic bullet, by which a induces pharmacological effects by interacting with a has been a strong driving force in pharmacology for a... (Review)
Review
Paul Ehrlich's concept of the magic bullet, by which a induces pharmacological effects by interacting with a has been a strong driving force in pharmacology for a century. It is continually thwarted, though, by the fact that the treated organism is highly dynamic and the target molecule(s) is (are) never static. In this article, we address some of the factors that modify and cause the mobility and plasticity of drug targets and their interactions with ligands and discuss how these can lead to unexpected (lack of) effects of drugs. These factors include genetic, epigenetic, and phenotypic variability, cellular plasticity, chronobiological rhythms, time, age and disease resolution, sex, drug metabolism, and distribution. We emphasize four existing approaches that can be taken, either singly or in combination, to try to minimize effects of pharmacological plasticity. These are firstly, to enhance specificity using target conditions close to those in diseases, secondly, by simultaneously or thirdly, sequentially aiming at multiple targets, and fourthly, in synchronization with concurrent dietary, psychological, training, and biorhythm-synchronizing procedures to optimize drug therapy.
Topics: Epigenesis, Genetic; Gene Expression Regulation; Humans; Ligands; Molecular Targeted Therapy; Pharmacology, Clinical
PubMed: 31768257
DOI: 10.1002/prp2.532 -
Frontiers in Plant Science 2022The liaison between Nitric oxide (NO) and phytohormones regulates a myriad of physiological processes at the cellular level. The interaction between NO and phytohormones... (Review)
Review
The liaison between Nitric oxide (NO) and phytohormones regulates a myriad of physiological processes at the cellular level. The interaction between NO and phytohormones is mainly influenced by NO-mediated post-translational modifications (PTMs) under basal as well as induced conditions. Protein S-nitrosylation is the most prominent and widely studied PTM among others. It is the selective but reversible redox-based covalent addition of a NO moiety to the sulfhydryl group of cysteine (Cys) molecule(s) on a target protein to form S-nitrosothiols. This process may involve either direct S-nitrosylation or indirect S-nitrosylation followed by transfer of NO group from one thiol to another (transnitrosylation). During S-nitrosylation, NO can directly target Cys residue (s) of key genes involved in hormone signaling thereby regulating their function. The phytohormones regulated by NO in this manner includes abscisic acid, auxin, gibberellic acid, cytokinin, ethylene, salicylic acid, jasmonic acid, brassinosteroid, and strigolactone during various metabolic and physiological conditions and environmental stress responses. S-nitrosylation of key proteins involved in the phytohormonal network occurs during their synthesis, degradation, or signaling roles depending upon the response required to maintain cellular homeostasis. This review presents the interaction between NO and phytohormones and the role of the canonical NO-mediated post-translational modification particularly, S-nitrosylation of key proteins involved in the phytohormonal networks under biotic and abiotic stresses.
PubMed: 35401598
DOI: 10.3389/fpls.2022.865542 -
Methods in Molecular Biology (Clifton,... 2022Quantitative structure-activity relationship (QSAR) models are routinely applied computational tools in the drug discovery process. QSAR models are regression or...
Quantitative structure-activity relationship (QSAR) models are routinely applied computational tools in the drug discovery process. QSAR models are regression or classification models that predict the biological activities of molecules based on the features derived from their molecular structures. These models are usually used to prioritize a list of candidate molecules for future laboratory experiments and to help chemists gain better insights into how structural changes affect a molecule's biological activities. Developing accurate and interpretable QSAR models is therefore of the utmost importance in the drug discovery process. Deep neural networks, which are powerful supervised learning algorithms, have shown great promise for addressing regression and classification problems in various research fields, including the pharmaceutical industry. In this chapter, we briefly review the applications of deep neural networks in QSAR modeling and describe commonly used techniques to improve model performance.
Topics: Drug Discovery; Neural Networks, Computer; Quantitative Structure-Activity Relationship
PubMed: 34731472
DOI: 10.1007/978-1-0716-1787-8_10 -
Biomedicine & Pharmacotherapy =... Sep 2023Plant bioactive molecules could play key preventive and therapeutic roles in chronological aging and the pathogenesis of many chronic diseases, often accompanied by... (Review)
Review
Plant bioactive molecules could play key preventive and therapeutic roles in chronological aging and the pathogenesis of many chronic diseases, often accompanied by increased oxidative stress and low-grade inflammation. Dietary antioxidants, including genkwanin, could decrease oxidative stress and the expression of pro-inflammatory cytokines or pathways. The present study is the first comprehensive review of genkwanin, a methoxyflavone found in several plant species. Indeed, natural sources, and pharmacokinetics of genkwanin, the biological properties were discussed and highlighted in detail. This review analyzed and considered all original studies related to identification, isolation, quantification, investigation of the biological and pharmacological properties of genkwanin. We consulted all published papers in peer-reviewed journals in the English language from the inception of each database to 12 May 2023. Different phytochemical demonstrated that genkwanin is a non-glycosylated flavone found and isolated from several medicinal plants such as Genkwa Flos, Rosmarinus officinalis, Salvia officinalis, and Leonurus sibiricus. In vitro and in vivo biological and pharmacological investigations showed that Genkwanin exhibits remarkable antioxidant and anti-inflammatory activities, genkwanin, via activation of glucokinase, has shown antihyperglycemic activity with a potential role against metabolic syndrome and diabetes. Additionally, it revealed cardioprotective and neuroprotective properties, thus reducing the risk of cardiovascular diseases and assisting against neurodegenerative diseases. Furthermore, genkwanin showed other biological properties like antitumor capability, antibacterial, antiviral, and dermato-protective effects. The involved mechanisms include sub-cellular, cellular and molecular actions at different levels such as inducing apoptosis and inhibiting the growth and proliferation of cancer cells. Despite the findings from preclinical studies that have demonstrated the effects of genkwanin and its diverse mechanisms of action, additional research is required to comprehensively explore its therapeutic potential. Primarily, extensive studies should be carried out to enhance our understanding of the molecule's pharmacodynamic actions and pharmacokinetic pathways. Moreover, toxicological and clinical investigations should be undertaken to assess the safety and clinical efficacy of genkwanin. These forthcoming studies are of utmost importance in fully unlocking the potential of this molecule in the realm of therapeutic applications.
Topics: Flavones; Anti-Inflammatory Agents; Cytokines; Plant Extracts; Antioxidants
PubMed: 37481929
DOI: 10.1016/j.biopha.2023.115159 -
Methods in Molecular Biology (Clifton,... 2022ADMET (absorption, distribution, metabolism, excretion, and toxicity) describes a drug molecule's pharmacokinetics and pharmacodynamics properties. ADMET profile of a...
ADMET (absorption, distribution, metabolism, excretion, and toxicity) describes a drug molecule's pharmacokinetics and pharmacodynamics properties. ADMET profile of a bioactive compound can impact its efficacy and safety. Moreover, efficacy and safety are considered some of the major causes of clinical attrition in the development of new chemical entities. In past decades, various machine learning or quantitative structure-activity relationship (QSAR) methods have been successfully integrated in the modeling of ADMET. Recent advances have been made in the collection of data and the development of various in silico methods to assess and predict ADMET of bioactive compounds in the early stages of drug discovery and development process.
Topics: Computer Simulation; Drug Discovery; Machine Learning; Quantitative Structure-Activity Relationship
PubMed: 34731482
DOI: 10.1007/978-1-0716-1787-8_20 -
Expert Opinion on Drug Delivery 2023The blood-brain barrier (BBB) restricts brain access of virtually all macromolecules. Receptor-mediated transcytosis (RMT) is one strategy toward their brain delivery.... (Review)
Review
INTRODUCTION
The blood-brain barrier (BBB) restricts brain access of virtually all macromolecules. Receptor-mediated transcytosis (RMT) is one strategy toward their brain delivery. In this strategy, targeting ligands conjugated to therapeutic payload or decorating particles containing the payload interact with targets on brain capillary endothelial cells (BCEC), triggering internalization, trafficking, and release from BCEC.
AREAS COVERED
RMT at the BBB has leveraged multiple formats of macromolecules and large particles. Interactions between those and BCEC have been studied primarily using antibodies, with findings applicable to the design of larger particles. BBB-penetrant constructs have also been identified in screening campaigns and directed evolution, and subsequently found to interact with RMT targets. In addition, BCEC targeted by constructs incorporating genomic payload can be made to produce therapeutic proteins.
EXPERT OPINION
While targeting may not be strictly necessary to reach a therapeutic effect for all macromolecules, it can improve a molecule's BBB transport, exposing it to the entire brain parenchyma and enhancing its effect. Constructs with better BCEC transcytosis may be designed rationally, leveraging knowledge about BCEC trafficking, and found in screening campaigns, where this knowledge can reduce the search space and improve iterative refinement. Identification of new targets may also help generate BBB-crossing constructs.
Topics: Blood-Brain Barrier; Endothelial Cells; Brain; Transcytosis; Biological Transport
PubMed: 37658673
DOI: 10.1080/17425247.2023.2255138 -
World Journal of Microbiology &... Mar 2020The recent scientific progresses on the use of enzyme-mediated reactions in organic, non-aqueous and aqueous media have significantly supported the growing demand of new... (Review)
Review
The recent scientific progresses on the use of enzyme-mediated reactions in organic, non-aqueous and aqueous media have significantly supported the growing demand of new biotechnological and/or pharmacological products. Today, a plethora of microbial enzymes, used as biocatalysts, are available. Among these, microbial transglutaminases (MTGs) are broadly used for their ability to catalyse the formation of an isopeptide bond between the γ-amide group of glutamines and the ε-amino group of lysine. Due to their promiscuity towards primary amine-containing substrates and the more stringent specificity for glutamine-containing peptide sequences, several combined approaches can be tailored for different settings, making MTGs very attractive catalysts for generating protein-protein and protein small molecule's conjugates. The present review offers a recent update on the modifications attainable by MTG-catalysed bioreactions as reported between 2014 and 2019. In particular, we present a detailed and comparative overview on the MTG-based methods for proteins and antibodies engineering, with a particular outlook on the synthesis of homogeneous antibody-drug conjugates.
Topics: Bacteria; Bacterial Proteins; Biocatalysis; Biotechnology; Fungal Proteins; Fungi; Immunoconjugates; Protein Engineering; Substrate Specificity; Transglutaminases
PubMed: 32172335
DOI: 10.1007/s11274-020-02829-y -
Journal of Molecular Recognition : JMR Dec 2019This review describes selected basics of water in biomolecular recognition. We focus on a qualitative understanding of the most important physical aspects, how these... (Review)
Review
This review describes selected basics of water in biomolecular recognition. We focus on a qualitative understanding of the most important physical aspects, how these change in magnitude between bulk water and protein environment, and how the roles that water plays for proteins arise from them. These roles include mechanical support, thermal coupling, dielectric screening, mass and charge transport, and the competition with a ligand for the occupation of a binding site. The presence or absence of water has ramifications that range from the thermodynamic binding signature of a single ligand up to cellular survival. The large inhomogeneity in water density, polarity and mobility around a solute is hard to assess in experiment. This is a source of many difficulties in the solvation of protein models and computational studies that attempt to elucidate or predict ligand recognition. The influence of water in a protein binding site on the experimental enthalpic and entropic signature of ligand binding is still a point of much debate. The strong water-water interaction in enthalpic terms is counteracted by a water molecule's high mobility in entropic terms. The complete arrest of a water molecule's mobility sets a limit on the entropic contribution of a water displacement process, while the solvent environment sets limits on ligand reactivity.
Topics: Binding Sites; Hydrogen Bonding; Ligands; Proteins; Water
PubMed: 31456282
DOI: 10.1002/jmr.2810 -
Journal of the American Chemical Society Oct 2022We achieved a concise total synthesis of salimabromide by using a novel intramolecular radical cyclization to simultaneously construct the unique benzo-fused [4.3.1]...
We achieved a concise total synthesis of salimabromide by using a novel intramolecular radical cyclization to simultaneously construct the unique benzo-fused [4.3.1] carbon skeleton and the vicinal quaternary stereocenters. Other notable transformations include a tandem Michael/Mukaiyama aldol reaction to introduce most of the molecule's structural elements, along with hidden information for late-stage transformations, an intriguing tandem oxidative cyclization of a diene to form the bridged butyrolactone and enone moieties spontaneously, and a highly enantioselective hydrogenation of a cycloheptenone derivative (97% ee) that paved the way for the asymmetric synthesis of salimabromide.
Topics: Stereoisomerism; Cyclization; Heterocyclic Compounds, 4 or More Rings; Carbon
PubMed: 36194507
DOI: 10.1021/jacs.2c08337 -
Pharmaceuticals (Basel, Switzerland) Aug 2021Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of... (Review)
Review
Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.
PubMed: 34577547
DOI: 10.3390/ph14090848