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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 -
Biology of Reproduction Apr 2015When mares are inseminated repeatedly, protein molecules from the seminal plasma (SP) prevent sperm-neutrophil binding and reduced fertility. The molecule(s) responsible...
When mares are inseminated repeatedly, protein molecules from the seminal plasma (SP) prevent sperm-neutrophil binding and reduced fertility. The molecule(s) responsible for sperm-neutrophil binding is not known and the identification of beneficial SP proteins is complicated by their large numbers and abundant variation. We examined several important aspects of sperm-neutrophil binding to ultimately facilitate the identification and isolation of the molecule(s) responsible. First, we raised anti-equine P-selectin antibodies to determine the involvement of this adhesion molecule in sperm-neutrophil binding. While these antibodies identified equine P-selectin, they did not inhibit sperm-neutrophil binding. However, acrosome-reacted equine sperm expressed a molecule similar to the ligand recognition unit of P-selectin. Second, we attempted to characterize SP protein binding to equine sperm and gauge their affinity. Biotinylated SP proteins were incubated with fresh sperm, washed over a viscous medium, electrophoresed, and probed with avidin. Several SP proteins bound to sperm with a strong affinity to withstand these treatments. This finding may prove valuable for future attempts to identify and characterize specific SP molecules. Lastly, we compared the secretions from male sex organs/glands on sperm motility, sperm-neutrophil binding, and their protein profile. We expected fewer proteins from individual organs/glands, which would facilitate isolation and identification of target molecules. While each secretion had a varying effect on motility and sperm-neutrophil binding, the protein profile was as complex as that seen in whole SP, indicating that collection of proteins from individual sources will not facilitate this work. Together, these experiments answer several important questions related to sperm-neutrophil binding, sperm-SP proteins interaction, and the complexity of the SP proteome.
Topics: Acrosome Reaction; Animals; Biotinylation; Epididymis; Genitalia, Male; Horses; In Vitro Techniques; Ligands; Male; Neutrophils; P-Selectin; Seminal Plasma Proteins; Sperm Motility; Spermatozoa; Testis
PubMed: 25695722
DOI: 10.1095/biolreprod.114.122655 -
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 May 2022Carbon dioxide (CO) impacts every aspect of life, and numerous sensing technologies have been established to detect and monitor this ubiquitous molecule. However, its...
Carbon dioxide (CO) impacts every aspect of life, and numerous sensing technologies have been established to detect and monitor this ubiquitous molecule. However, its selective sensing at the molecular level remains an unmet challenge, despite the tremendous potential of such an approach for understanding this molecule's role in complex environments. In this work, we introduce a unique class of selective fluorescent carbon dioxide molecular sensors (CarboSen) that addresses these existing challenges through an activity-based approach. Besides the design, synthesis, and evaluation of these small molecules as CO sensors, we demonstrate their utility by tailoring their reactivity and optical properties, allowing their use in a broad spectrum of multidisciplinary applications, including atmospheric sensing, chemical reaction monitoring, enzymology, and live-cell imaging. Collectively, these results showcase the potential of CarboSen sensors as broadly applicable tools to monitor and visualize carbon dioxide across multiple disciplines.
Topics: Carbon Dioxide
PubMed: 35503368
DOI: 10.1021/jacs.2c02361 -
Journal of Genetics Jul 2018Tauopathies represent a group of neurodegenerative disorder which are characterized by the presence of tau positive specialized argyrophilic and insoluble intraneuronal... (Review)
Review
Tauopathies represent a group of neurodegenerative disorder which are characterized by the presence of tau positive specialized argyrophilic and insoluble intraneuronal and glial fibrillar lesions known as neurofibrillary tangles (NFTs). Tau is a neuron specific microtubule binding protein which is required for the integrity and functioning of neuronal cells, and hyperphosphorylation of tau and its subsequent aggregation and paired helical filaments (PHFs) and NFTs has emerged as one of the major pathogenic mechanisms of tauopathies in human and mammalian model systems. Modeling of human tauopathies in results in manifestation of associated phenotypes, and a recent study has demonstrated that similar to human and mammalian models, accumulation of insoluble tau aggregates in the form of typical neurotoxic NFTs triggers the pathogenesis of tauopathies in fly models. In view of the availability of remarkable genetic tools, tau models could be extremely useful for in-depth analysis of the role of NFTs in neurodegeneration and tau aetiology, and also for the screening of novel gene(s) and molecule(s) which suppress the toxicity of tau aggregates.
Topics: Animals; Disease Models, Animal; Drosophila melanogaster; Humans; Neurofibrillary Tangles; Neurons; Tauopathies; tau Proteins
PubMed: 30027909
DOI: No ID Found -
Progress in Lipid Research Jan 2018Steroidal alkaloids (SAs) are widely synthesized and distributed in plants manifesting as natural produce endowed with potential for medicinal, pesticidal and other... (Review)
Review
Steroidal alkaloids (SAs) are widely synthesized and distributed in plants manifesting as natural produce endowed with potential for medicinal, pesticidal and other high-value usages. Glycosylation of these SAs raises complex and diverse glycosides in plant cells that indeed govern numerous functional aspects. During the glycosylation process of these valuable metabolites, the addition of carbohydrate molecule(s) is catalyzed by enzymes known as sterol glycosyltransferases (SGTs), commonly referred to as UGTs, leading to the production of steryl glycosides (SGs). The ratio of SGs and nonglyco-conjugated SAs are different in different plant species, however, their biosynthesis in the cell is controlled by different environmental factors. The aim of this review is to evaluate the current SGT enzyme research and the functional consequences of glycomodification of SAs on the physiology and plant development, which together are associated with the plant's primary processes. Pharmaceutical, industrial, and other potential uses of saponins have also been discussed and their use in therapeutics has been unveiled by in silico analysis. The field of biotransformation or conversion of nonglycosylated to glycosylated phytosterols by the activity of SGTs, making them soluble, available and more useful for humankind is the new field of interest towards drug therapy.
Topics: Alkaloids; Amino Acid Sequence; Evolution, Molecular; Glycosyltransferases; Humans; Plant Development; Sterols
PubMed: 29170003
DOI: 10.1016/j.plipres.2017.11.001 -
Frontiers in Pharmacology 2022The human microbiota produces molecules that are evolved to interact with the diverse cellular machinery of both the host and microbes, mediating health and diseases.... (Review)
Review
The human microbiota produces molecules that are evolved to interact with the diverse cellular machinery of both the host and microbes, mediating health and diseases. One of the most puzzling microbiome molecules is colibactin, a genotoxin encoded in some commensal and extraintestinal microbes and is implicated in initiating colorectal cancer. The colibactin cluster was discovered more than 15 years ago, and most of the research studies have been focused on revealing the biosynthesis and precise structure of the cryptic encoded molecule(s) and the mechanism of carcinogenesis. In 2022, the Balskus group revealed that colibactin not only hits targets in the eukaryotic cell machinery but also in the prokaryotic cell. To that end, colibactin crosslinks the DNA resulting in activation of the SOS signaling pathway, leading to prophage induction from bacterial lysogens and modulation of virulence genes in pathogenic species. These unique activities of colibactin highlight its ecological role in shaping gut microbial communities and further consequences that impact human health. This review dives in-depth into the molecular mechanisms underpinning colibactin cellular targets in eukaryotic and prokaryotic cells, aiming to understand the fine details of the role of secreted microbiome chemistry in mediating host-microbe and microbe-microbe interactions. This understanding translates into a better realization of microbiome potential and how this could be advanced to future microbiome-based therapeutics or diagnostic biomarkers.
PubMed: 36172175
DOI: 10.3389/fphar.2022.958012 -
The FEBS Journal May 2023Drugs interact with their target of interest to bring about the desired phenotypic outcome that results in disease alleviation. Traditionally, most lead optimization... (Review)
Review
Drugs interact with their target of interest to bring about the desired phenotypic outcome that results in disease alleviation. Traditionally, most lead optimization exercises were driven by affinity measures (like IC ) to inform structure-activity relationship (SAR)-guided medicinal chemistry. However, an IC value is a thermodynamic estimate measured under equilibrium conditions that can vary as a function of substrate concentration and/or time (the latter especially for nonequilibrium modalities). Further, like other thermodynamic estimates, it is a state-function that is indifferent to the path traversed from the initial state to the final state. This can be a cause for concern in drug discovery given the predominance of nonequilibrium interactions and the open thermodynamic nature of the human system. Under such situations, employing rates along with equilibrium constants (or IC values) would be far more relevant to capture the time evolution of the small molecule's interaction with the target of interest. These rates are generally typified by the rate of association, rate of dissociation and the residence time of the small molecule on the target (target occupancy). These parameters, when combined with the concept of target vulnerability, therapeutic window, pharmacokinetic profile of the small molecule, estimates of endogenous ligand and target turnover, will shed critical insights into the kinetics and dynamics of a small molecule's interaction with the protein, and allow realistic modelling of the system to enable optimizations and dosing decisions. With that aim, this guide will attempt to introduce the traditional role of mechanistic enzymology within drug discovery and emphasize the importance of kinetics in guiding SAR-based optimizations. It will also present initial ideas on how kinetic investigation should be positioned relative to the temporal span of a drug-discovery pipeline to leverage maximal utility from the investment in time and effort.
Topics: Humans; Kinetics; Structure-Activity Relationship; Proteins; Physics; Drug Discovery
PubMed: 35175693
DOI: 10.1111/febs.16404