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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 -
Frontiers For Young Minds May 2022RNA, like its close cousin DNA, is used to store information in the cell. Unlike DNA, it is really good at folding up into interesting shapes, which makes it good at...
RNA, like its close cousin DNA, is used to store information in the cell. Unlike DNA, it is really good at folding up into interesting shapes, which makes it good at lots of other important jobs. Some kinds of RNA, called riboswitches, can sense what is going on inside a cell. Each riboswitch fits a specific small molecule. When the riboswitch and small molecule interact it changes what the cell does. For example, if the small molecule is harmful the cell might start making a protein that will get rid of it. Recently, scientists discovered some riboswitches that look very similar to each other but recognize very different small molecules. We used X-ray crystallography to get pictures of these riboswitches. We saw how changing just one piece of the riboswitch changed which small molecule it recognized. This shows us how RNA can gain new functions as an organism evolves.
PubMed: 36909261
DOI: 10.3389/frym.2022.686804 -
Biosensors Aug 2022Self-assembled biomaterials have been widely explored for real-time fluorescence imaging, imaging-guided surgery, and targeted therapy for tumors, etc. In particular,... (Review)
Review
Self-assembled biomaterials have been widely explored for real-time fluorescence imaging, imaging-guided surgery, and targeted therapy for tumors, etc. In particular, small molecule-based self-assembly has been established as a reliable strategy for cancer theranostics due to the merits of small-sized molecules, multiple functions, and ease of synthesis and modification. In this review, we first briefly introduce the supramolecular chemistry of small organic molecules in cancer theranostics. Then, we summarize and discuss advanced small molecule-based self-assembly for cancer theranostics based on three types, including peptides, amphiphilic molecules, and aggregation-induced emission luminogens. Finally, we conclude with a perspective on future developments of small molecule-based self-assembled biomaterials integrating diagnosis and therapy for biomedical applications. These applications highlight the opportunities arising from the rational design of small organic molecules with self-assembly properties for precision medicine.
Topics: Biocompatible Materials; Humans; Neoplasms; Peptides; Precision Medicine; Theranostic Nanomedicine
PubMed: 36140068
DOI: 10.3390/bios12090683 -
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 -
Cell Proliferation Jun 2024Osteoarthritis (OA) is the most prevalent disorder of synovial joint affecting multiple joints. In the past decade, we have witnessed conceptual switch of OA... (Review)
Review
Osteoarthritis (OA) is the most prevalent disorder of synovial joint affecting multiple joints. In the past decade, we have witnessed conceptual switch of OA pathogenesis from a 'wear and tear' disease to a disease affecting entire joint. Extensive studies have been conducted to understand the underlying mechanisms of OA using genetic mouse models and ex vivo joint tissues derived from individuals with OA. These studies revealed that multiple signalling pathways are involved in OA development, including the canonical Wnt/β-catenin signalling and its interaction with other signalling pathways, such as transforming growth factor β (TGF-β), bone morphogenic protein (BMP), Indian Hedgehog (Ihh), nuclear factor κB (NF-κB), fibroblast growth factor (FGF), and Notch. The identification of signalling interaction and underlying mechanisms are currently underway and the specific molecule(s) and key signalling pathway(s) playing a decisive role in OA development need to be evaluated. This review will focus on recent progresses in understanding of the critical role of Wnt/β-catenin signalling in OA pathogenesis and interaction of β-catenin with other pathways, such as TGF-β, BMP, Notch, Ihh, NF-κB, and FGF. Understanding of these novel insights into the interaction of β-catenin with other pathways and its integration into a complex gene regulatory network during OA development will help us identify the key signalling pathway of OA pathogenesis leading to the discovery of novel therapeutic strategies for OA intervention.
Topics: Humans; Osteoarthritis; Animals; beta Catenin; Signal Transduction; Wnt Signaling Pathway; NF-kappa B; Hedgehog Proteins; Bone Morphogenetic Proteins; Transforming Growth Factor beta
PubMed: 38199244
DOI: 10.1111/cpr.13600 -
Journal of Medicinal Chemistry May 2022The canonical Wingless-related integration site signaling pathway plays a critical role in human physiology, and its dysregulation can lead to an array of diseases.... (Review)
Review
The canonical Wingless-related integration site signaling pathway plays a critical role in human physiology, and its dysregulation can lead to an array of diseases. β-Catenin is a multifunctional protein within this pathway and an attractive yet challenging therapeutic target, most notably in oncology. This has stimulated the search for potent small-molecule inhibitors binding directly to the β-catenin surface to inhibit its protein-protein interactions and downstream signaling. Here, we provide an account of the claimed (and some putative) small-molecule ligands of β-catenin from the literature. Through in silico analysis, we show that most of these molecules contain promiscuous chemical substructures notorious for interfering with screening assays. Finally, and in line with this analysis, we demonstrate using orthogonal biophysical techniques that none of the examined small molecules bind at the surface of β-catenin. While shedding doubts on their reported mode of action, this study also reaffirms β-catenin as a prominent target in drug discovery.
Topics: Animals; Biophysical Phenomena; Drug Discovery; Humans; Small Molecule Libraries; Wnt Signaling Pathway; beta Catenin
PubMed: 35581674
DOI: 10.1021/acs.jmedchem.2c00228 -
Nature Chemistry Aug 2021Homochiral membrane bilayers organize biological functions in all domains of life. The membrane's permeability-its key property-correlates with a molecule's...
Homochiral membrane bilayers organize biological functions in all domains of life. The membrane's permeability-its key property-correlates with a molecule's lipophilicity, but the role of the membrane's rich and uniform stereochemistry as a permeability determinant is largely ignored in empirical and computational measurements. Here, we describe a new approach to measuring permeation using continuously generated microfluidic droplet interface bilayers (DIBs, generated at a rate of 480 per minute) and benchmark this system by monitoring fluorescent dye DIB permeation over time. Enantioselective permeation of alkyne-labelled amino acids (Ala, Val, Phe, Pro) and dipeptides through a chiral phospholipid bilayer was demonstrated using DIB transport measurements; the biological L enantiomers permeated faster than the D enantiomers (from 1.2-fold to 6-fold for Ala to Pro). Enantioselective permeation both poses a potentially unanticipated criterion for drug design and offers a kinetic mechanism for the abiotic emergence of homochirality via chiral transfer between sugars, amino acids and lipids.
Topics: Alkynes; Amino Acids; Cholesterol; Fluorescent Dyes; Lipid Bilayers; Permeability; Phosphatidylcholines; Stereoisomerism
PubMed: 34112989
DOI: 10.1038/s41557-021-00708-z -
Artificial Intelligence in the Life... Dec 2022Anyone involved in designing or finding molecules in the life sciences over the past few years has witnessed a dramatic change in how we now work due to the COVID-19...
Anyone involved in designing or finding molecules in the life sciences over the past few years has witnessed a dramatic change in how we now work due to the COVID-19 pandemic. Computational technologies like artificial intelligence (AI) seemed to become ubiquitous in 2020 and have been increasingly applied as scientists worked from home and were separated from the laboratory and their colleagues. This shift may be more permanent as the future of molecule design across different industries will increasingly require machine learning models for design and optimization of molecules as they become "designed by AI". AI and machine learning has essentially become a commodity within the pharmaceutical industry. This perspective will briefly describe our personal opinions of how machine learning has evolved and is being applied to model different molecule properties that crosses industries in their utility and ultimately suggests the potential for tight integration of AI into equipment and automated experimental pipelines. It will also describe how many groups have implemented generative models covering different architectures, for design of molecules. We also highlight some of the companies at the forefront of using AI to demonstrate how machine learning has impacted and influenced our work. Finally, we will peer into the future and suggest some of the areas that represent the most interesting technologies that may shape the future of molecule design, highlighting how we can help increase the efficiency of the design-make-test cycle which is currently a major focus across industries.
PubMed: 36211981
DOI: 10.1016/j.ailsci.2022.100031 -
Proceedings of SPIE--the International... Aug 2022Advances in nanotechnology enable the detection of trace molecules from the enhanced Raman signal generated at the surface of plasmonic nanoparticles. We have developed...
Advances in nanotechnology enable the detection of trace molecules from the enhanced Raman signal generated at the surface of plasmonic nanoparticles. We have developed technology to enable super-resolution imaging of plasmonic nanoparticles, where the fluctuations in the surface enhanced Raman scattering (SERS) signal can be analyzed with localization microscopy techniques to provide nanometer spatial resolution of the emitting molecule's location. Additional work now enables the super-resolved SERS image and the corresponding spectrum to be acquired simultaneously. Here we will discuss how this approach can be applied to provide new insights into biological cells.
PubMed: 37431396
DOI: 10.1117/12.2632824 -
Proceedings of the National Academy of... Apr 2022Crystallography is the standard for determining the atomic structure of molecules. Unfortunately, many interesting molecules, including an extensive array of biological...
Crystallography is the standard for determining the atomic structure of molecules. Unfortunately, many interesting molecules, including an extensive array of biological macromolecules, do not form crystals. While ultrashort and intense X-ray pulses from free-electron lasers are promising for imaging single isolated molecules with the so-called “diffraction before destruction” technique, nanocrystals are still needed for producing sufficient scattering signal for structure retrieval as implemented in serial femtosecond crystallography. Here, we show that a femtosecond laser pulse train may be used to align an ensemble of isolated molecules to a high level transiently, such that the diffraction pattern from the highly aligned molecules resembles that of a single molecule, allowing one to retrieve its atomic structure with a coherent diffraction imaging technique. In our experiment with CO2 molecules, a high degree of alignment is maintained for about 100 fs, and a precisely timed ultrashort relativistic electron beam from a table-top instrument is used to record the diffraction pattern within that duration. The diffraction pattern is further used to reconstruct the distribution of CO2 molecules with atomic resolution. Our results mark a significant step toward imaging noncrystallized molecules with atomic resolution and open opportunities in the study and control of dynamics in the molecular frame that provide information inaccessible with randomly oriented molecules.
PubMed: 35385356
DOI: 10.1073/pnas.2122793119