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Current Opinion in Chemical Biology Aug 2017Small molecule probes of biological systems have traditionally been designed to bind to and inhibit the active sites of their protein targets. While this class of... (Review)
Review
Small molecule probes of biological systems have traditionally been designed to bind to and inhibit the active sites of their protein targets. While this class of pharmacological agents has been broadened by the development of a small number of allosteric and protein-protein interaction (PPI) inhibitors, conventional drug design still excludes 'undruggable' proteins that are neither enzymes nor receptors. Recent years have seen the emergence of new classes of small molecules that can target hitherto undruggable proteins by recruiting the cellular proteostasis machinery to selectively tag them for degradation. These molecules, especially the class known as Proteolysis Targeting Chimera (PROTACs), represent a paradigm shift in chemical genetics, but their most tantalizing potential is as novel therapeutic agents. This review briefly summarizes the preclinical development of small molecule-based protein degraders, and describes the recent improvements in the technology that have positioned PROTACs on the cusp of entering the clinic.
Topics: Amino Acid Sequence; Animals; Humans; Proteins; Proteolysis; Small Molecule Libraries
PubMed: 28605671
DOI: 10.1016/j.cbpa.2017.05.016 -
ACS Chemical Biology Jan 2011Small molecules are important not only as therapeutics to treat disease but also as chemical tools to probe complex biological processes. The discovery of novel... (Review)
Review
Small molecules are important not only as therapeutics to treat disease but also as chemical tools to probe complex biological processes. The discovery of novel bioactive small molecules has largely been catalyzed by screening diverse chemical libraries for alterations in specific activities in pure proteins assays or in generating cell-based phenotypes. New approaches are needed to close the vast gap between the ability to study either single proteins or whole cellular processes. This Review focuses on the growing number of studies aimed at understanding in more detail how small molecules perturb particular signaling pathways and larger networks to yield distinct cellular phenotypes. This type of pathway-level analysis and phenotypic profiling provides valuable insight into mechanistic action of small molecules and can reveal off-target effects and improve our understanding of how proteins within a pathway regulate signaling.
Topics: Drug Delivery Systems; Molecular Probes; Proteome; RNA Interference; Signal Transduction; Small Molecule Libraries
PubMed: 21087032
DOI: 10.1021/cb1002976 -
Wiley Interdisciplinary Reviews. RNA Nov 2016Highly conserved noncoding RNA (ncRNA) elements in viral genomes and transcripts offer new opportunities to expand the repertoire of drug targets for the development of... (Review)
Review
Highly conserved noncoding RNA (ncRNA) elements in viral genomes and transcripts offer new opportunities to expand the repertoire of drug targets for the development of antiinfective therapy. Ligands binding to ncRNA architectures are able to affect interactions, structural stability or conformational changes and thereby block processes essential for viral replication. Proof of concept for targeting functional RNA by small molecule inhibitors has been demonstrated for multiple viruses with RNA genomes. Strategies to identify antiviral compounds as inhibitors of ncRNA are increasingly emphasizing consideration of drug-like properties of candidate molecules emerging from screening and ligand design. Recent efforts of antiviral lead discovery for RNA targets have provided drug-like small molecules that inhibit viral replication and include inhibitors of human immunodeficiency virus (HIV), hepatitis C virus (HCV), severe respiratory syndrome coronavirus (SARS CoV), and influenza A virus. While target selectivity remains a challenge for the discovery of useful RNA-binding compounds, a better understanding is emerging of properties that define RNA targets amenable for inhibition by small molecule ligands. Insight from successful approaches of targeting viral ncRNA in HIV, HCV, SARS CoV, and influenza A will provide a basis for the future exploration of RNA targets for therapeutic intervention in other viral pathogens which create urgent, unmet medical needs. Viruses for which targeting ncRNA components in the genome or transcripts may be promising include insect-borne flaviviruses (Dengue, Zika, and West Nile) and filoviruses (Ebola and Marburg). WIREs RNA 2016, 7:726-743. doi: 10.1002/wrna.1373 For further resources related to this article, please visit the WIREs website.
Topics: Animals; Antiviral Agents; Humans; RNA, Viral; Small Molecule Libraries; Virus Replication
PubMed: 27307213
DOI: 10.1002/wrna.1373 -
Organic & Biomolecular Chemistry Sep 2021Nearly all FDA approved drugs and bioactive small molecules exert their effects by binding to and modulating proteins. Consequently, understanding how small molecules... (Review)
Review
Nearly all FDA approved drugs and bioactive small molecules exert their effects by binding to and modulating proteins. Consequently, understanding how small molecules interact with proteins at an molecular level is a central challenge of modern chemical biology and drug development. Complementary to structure-guided approaches, chemoproteomics has emerged as a method capable of high-throughput identification of proteins covalently bound by small molecules. To profile noncovalent interactions, established chemoproteomic workflows typically incorporate photoreactive moieties into small molecule probes, which enable trapping of small molecule-protein interactions (SMPIs). This strategy, termed photoaffinity labelling (PAL), has been utilized to profile an array of small molecule interactions, including for drugs, lipids, metabolites, and cofactors. Herein we describe the discovery of photocrosslinking chemistries, including a comparison of the strengths and limitations of implementation of each chemotype in chemoproteomic workflows. In addition, we highlight key examples where photoaffinity labelling has enabled target deconvolution and interaction site mapping.
Topics: Photoaffinity Labels
PubMed: 34549230
DOI: 10.1039/d1ob01353j -
Current Opinion in Chemical Biology Feb 2015MicroRNAs (miRNAs) are small, non-coding RNAs that control protein expression. Aberrant miRNA expression has been linked to various human diseases, and thus miRNAs have... (Review)
Review
MicroRNAs (miRNAs) are small, non-coding RNAs that control protein expression. Aberrant miRNA expression has been linked to various human diseases, and thus miRNAs have been explored as diagnostic markers and therapeutic targets. Although it is challenging to target RNA with small molecules in general, there have been successful campaigns that have identified small molecule modulators of miRNA function by targeting various pathways. For example, small molecules that modulate transcription and target nuclease processing sites in miRNA precursors have been identified. Herein, we describe challenges in developing chemical probes that target miRNAs and highlight aspects of miRNA cellular biology elucidated by using small molecule chemical probes. We expect that this area will expand dramatically in the near future as progress is made in understanding small molecule recognition of RNA.
Topics: Animals; Base Sequence; Drug Discovery; Humans; MicroRNAs; Molecular Probe Techniques; Molecular Probes; Molecular Sequence Data; Small Molecule Libraries; Transcriptional Activation
PubMed: 25500006
DOI: 10.1016/j.cbpa.2014.10.024 -
The Journal of Biological Chemistry 2021Since the characterization of mRNA in 1961, our understanding of the roles of RNA molecules has significantly grown. Beyond serving as a link between DNA and proteins,... (Review)
Review
Since the characterization of mRNA in 1961, our understanding of the roles of RNA molecules has significantly grown. Beyond serving as a link between DNA and proteins, RNA molecules play direct effector roles by binding to various ligands, including proteins, DNA, other RNAs, and metabolites. Through these interactions, RNAs mediate cellular processes such as the regulation of gene transcription and the enhancement or inhibition of protein activity. As a result, the misregulation of RNA molecules is often associated with disease phenotypes, and RNA molecules have been increasingly recognized as potential targets for drug development efforts, which in the past had focused primarily on proteins. Although both small molecule-based and oligonucleotide-based therapies have been pursued in efforts to target RNA, small-molecule modalities are often favored owing to several advantages including greater oral bioavailability. In this review, we discuss three general frameworks (sets of premises and hypotheses) that, in our view, have so far dominated the discovery of small-molecule ligands for RNA. We highlight the unique merits of each framework as well as the pitfalls associated with exclusive focus of ligand discovery efforts within only one framework. Finally, we propose that RNA ligand discovery can benefit from using progress made within these three frameworks to move toward a paradigm that formulates RNA-targeting questions at the level of RNA structural subclasses.
Topics: Drug Discovery; Ligands; Nucleic Acid Conformation; RNA; Small Molecule Libraries
PubMed: 33334887
DOI: 10.1074/jbc.REV120.015203 -
Accounts of Chemical Research May 2021Rigorous substrate selectivity is a hallmark of enzyme catalysis. This selectivity is generally ascribed to a thermodynamically favorable process of substrate binding to... (Review)
Review
Rigorous substrate selectivity is a hallmark of enzyme catalysis. This selectivity is generally ascribed to a thermodynamically favorable process of substrate binding to the enzyme active site based upon complementary physiochemical characteristics, which allows both acquisition and orientation. However, this chemical selectivity is more difficult to rationalize for diminutive molecules that possess too narrow a range of physical characteristics to allow either precise positioning or discrimination between a substrate and an inhibitor. Foremost among these small molecules are dissolved gases such as H, N, O, CO, CO, NO, NO, NH, and CH so often encountered in metalloenzyme catalysis. Nevertheless, metalloenzymes have evolved to metabolize these small-molecule substrates with high selectivity and efficiency.The soluble methane monooxygenase enzyme (sMMO) acts upon two of these small molecules, O and CH, to generate methanol as part of the C1 metabolic pathway of methanotrophic organisms. sMMO is capable of oxidizing many alternative hydrocarbon substrates. Remarkably, however, it will preferentially oxidize methane, the substrate with the fewest discriminating physical characteristics and the strongest C-H bond. Early studies led us to broadly attribute this specificity to the formation of a "molecular sieve" in which a methane- and oxygen-sized tunnel provides a size-selective route from bulk solvent to the completely buried sMMO active site. Indeed, recent cryogenic and serial femtosecond ambient temperature crystallographic studies have revealed such a route in sMMO. A detailed study of the sMMO tunnel considered here in the context of small-molecule tunnels identified in other metalloenzymes reveals three discrete characteristics that contribute to substrate selectivity and positioning beyond that which can be provided by the active site itself. Moreover, the dynamic nature of many tunnels allows an exquisite coordination of substrate binding and reaction phases of the catalytic cycle. Here we differentiate between the highly selective molecular tunnel, which allows only the one-dimensional transit of small molecules, and the larger, less-selective channels found in typical enzymes. Methods are described to identify and characterize tunnels as well as to differentiate them from channels. In metalloenzymes which metabolize dissolved gases, we posit that the contribution of tunnels is so great that they should be considered to be extensions of the active site itself. A full understanding of catalysis by these enzymes requires an appreciation of the roles played by tunnels. Such an understanding will also facilitate the use of the enzymes or their synthetic mimics in industrial or pharmaceutical applications.
Topics: Biocatalysis; Catalytic Domain; Metalloproteins; Models, Molecular; Oxygenases; Small Molecule Libraries
PubMed: 33886257
DOI: 10.1021/acs.accounts.1c00058 -
PLoS Computational Biology Mar 2022Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules...
Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPIs is challenging, however, because many potential drug-binding sites at PPI interfaces are "cryptic": When unoccupied by a ligand, cryptic sites are often flat and featureless, and thus not readily recognizable in crystal structures, with the geometric and chemical characteristics of typical small-molecule binding sites only emerging upon ligand binding. The rational design of small molecules to inhibit specific PPIs would benefit from a better understanding of how such molecules bind at PPI interfaces. To this end, we have conducted unbiased, all-atom MD simulations of the binding of four small-molecule inhibitors (SP4206 and three SP4206 analogs) to interleukin 2 (IL2)-which performs its function by forming a PPI with its receptor-without incorporating any prior structural information about the ligands' binding. In multiple binding events, a small molecule settled into a stable binding pose at the PPI interface of IL2, resulting in a protein-small-molecule binding site and pose virtually identical to that observed in an existing crystal structure of the IL2-SP4206 complex. Binding of the small molecule stabilized the IL2 binding groove, which when the small molecule was not bound emerged only transiently and incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between the native and non-native IL2-small-molecule binding poses found in the simulations, suggesting that binding simulations in combination with FEP may provide an effective tool for identifying cryptic binding sites and determining the binding poses of small molecules designed to disrupt PPI interfaces by binding to such sites.
Topics: Binding Sites; Drug Discovery; Interleukin-2; Ligands; Protein Binding
PubMed: 35239648
DOI: 10.1371/journal.pcbi.1009817 -
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 -
Theranostics 2019With further research into the molecular mechanisms and roles linking immune suppression and restraint of (pre)malignancies, immunotherapies have revolutionized clinical... (Review)
Review
With further research into the molecular mechanisms and roles linking immune suppression and restraint of (pre)malignancies, immunotherapies have revolutionized clinical strategies in the treatment of cancer. However, nearly 70% of patients who received immune checkpoint therapeutics showed no response. Complementary and/or synergistic effects may occur when extracellular checkpoint antibody blockades combine with small molecules targeting intracellular signal pathways up/downstream of immune checkpoints or regulating the innate and adaptive immune response. After radiolabeling with radionuclides, small molecules can also be used for estimating treatment efficacy of immune checkpoint blockades. This review not only highlights some significant intracellular pathways and immune-related targets such as the kynurenine pathway, purinergic signaling, the kinase signaling axis, chemokines, etc., but also summarizes some attractive and potentially immunosuppression-related small molecule agents, which may be synergistic with extracellular immune checkpoint blockade. In addition, opportunities for small molecule-based theranostics in cancer immunology will be discussed.
Topics: Animals; Humans; Immune System; Immunotherapy; Neoplasms; Small Molecule Libraries; Theranostic Nanomedicine
PubMed: 31695804
DOI: 10.7150/thno.37218