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Scientific Reports Mar 2017To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the...
To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
Topics: Drug Discovery; Small Molecule Libraries; Software
PubMed: 28256516
DOI: 10.1038/srep42717 -
Nature Communications Mar 2019Protein-protein interactions (PPIs) governing the recognition of substrates by E3 ubiquitin ligases are critical to cellular function. There is significant therapeutic...
Protein-protein interactions (PPIs) governing the recognition of substrates by E3 ubiquitin ligases are critical to cellular function. There is significant therapeutic potential in the development of small molecules that modulate these interactions; however, rational design of small molecule enhancers of PPIs remains elusive. Herein, we report the prospective identification and rational design of potent small molecules that enhance the interaction between an oncogenic transcription factor, β-Catenin, and its cognate E3 ligase, SCF. These enhancers potentiate the ubiquitylation of mutant β-Catenin by β-TrCP in vitro and induce the degradation of an engineered mutant β-Catenin in a cellular system. Distinct from PROTACs, these drug-like small molecules insert into a naturally occurring PPI interface, with contacts optimized for both the substrate and ligase within the same small molecule entity. The prospective discovery of 'molecular glue' presented here provides a paradigm for the development of small molecule degraders targeting hard-to-drug proteins.
Topics: HEK293 Cells; Humans; Phosphorylation; Protein Binding; Proteolysis; Small Molecule Libraries; Substrate Specificity; Ubiquitin-Protein Ligases; Ubiquitination; beta Catenin; beta-Transducin Repeat-Containing Proteins
PubMed: 30926793
DOI: 10.1038/s41467-019-09358-9 -
Methods in Molecular Biology (Clifton,... 2015Drug affinity responsive target stability (DARTS) is a relatively quick and straightforward approach to identify potential protein targets for small molecules. It relies...
Drug affinity responsive target stability (DARTS) is a relatively quick and straightforward approach to identify potential protein targets for small molecules. It relies on the protection against proteolysis conferred on the target protein by interaction with a small molecule. The greatest advantage of this method is being able to use the native small molecule without having to immobilize or modify it (e.g., by incorporation of biotin, fluorescent, radioisotope, or photoaffinity labels). Here we describe in detail the protocol for performing unbiased DARTS with complex protein lysates to identify binding targets of small molecules and for using DARTS-Western blotting to test, screen, or validate potential small-molecule targets. Although the ideas have mainly been developed from studying molecules in areas of biology that are currently of interest to us and our collaborators, the general principles should be applicable to the analysis of all molecules in nature.
Topics: Ligands; Protein Binding; Proteins; Proteomics; Reproducibility of Results; Small Molecule Libraries
PubMed: 25618353
DOI: 10.1007/978-1-4939-2269-7_22 -
Molecules (Basel, Switzerland) Aug 2022Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively... (Review)
Review
Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.
Topics: Drug Development; Immunotherapy; Neoplasms; Proteolysis
PubMed: 36080223
DOI: 10.3390/molecules27175439 -
Cellular and Molecular Life Sciences :... Mar 2021As a naturally occurring class of gene regulators, microRNAs (miRNAs) have attracted much attention as promising targets for therapeutic development. However, RNAs... (Review)
Review
As a naturally occurring class of gene regulators, microRNAs (miRNAs) have attracted much attention as promising targets for therapeutic development. However, RNAs including miRNAs have long been considered undruggable, and most efforts have been devoted to using synthetic oligonucleotides to regulate miRNAs. Encouragingly, recent findings have revealed that miRNAs can also be drugged with small molecules that directly target miRNAs. In this review paper, we give a summary of recently emerged small-molecule inhibitors (SMIs) and small-molecule degraders (SMDs) for miRNAs. SMIs are small molecules that directly bind to miRNAs to inhibit their biogenesis, and SMDs are bifunctional small molecules that upon binding to miRNAs induce miRNA degradation. Strategies for discovering SMIs and developing SMDs were summarized. Applications of SMIs and SMDs in miRNA inhibition and cancer therapy were also introduced. Overall, SMIs and SMDs introduced here have high potency and specificity in miRNA inhibition. We envision that these small molecules will pave the way for developing novel therapeutics toward miRNAs that were previously considered undruggable.
Topics: Animals; Gene Expression Regulation; High-Throughput Screening Assays; Humans; MicroRNAs; Molecular Structure; Nucleic Acid Conformation; RNA Stability; Small Molecule Libraries
PubMed: 33052435
DOI: 10.1007/s00018-020-03676-8 -
SLAS Discovery : Advancing Life... Apr 2021Targeted protein degradation (TPD) is a recent strategy, utilizing the cell's proteostasis machinery to deplete specific proteins. This represents a paradigm shift in... (Review)
Review
Targeted protein degradation (TPD) is a recent strategy, utilizing the cell's proteostasis machinery to deplete specific proteins. This represents a paradigm shift in early drug discovery, away from occupancy-driven to event-driven mechanisms.Recent efforts have focused on the development of proteolysis-targeting chimeras (PROTACs). These heterobifunctional molecules combine a target-specific binding moiety linked to an E3 ligase ligand and trigger selective ubiquitination of the target protein, marking it for proteasomal degradation. While these molecules can be highly efficacious, they generally have unfavorable physicochemical properties due to their large size.In contrast, smaller molecules that induce degradation could represent an attractive, simple option to overcoming the limitations of both traditional modulators and PROTACs. These molecules may have a range of mechanisms: recruitment of an E3 ligase (molecular glues), introduction of hydrophobic areas, or inducing local unfolding, each of which triggers degradation.We recently completed a high-throughput screen of 111,000 compounds in a cellular HiBiT assay in an effort to identify such molecules. Preliminary analysis indicates that we have been able to identify alternative small-molecule degraders. We highlight methods for triage, characterization, selectivity, and mode of action. In summary, we believe that these types of small-molecule degraders, which may possibly have more acceptable physicochemical properties than the inherently larger heterobifunctional molecules, are an exciting approach for inducing TPD, and we illustrate that a general screening approach can be successful in identifying useful start points for developing such molecules.
Topics: Drug Discovery; Eukaryotic Cells; High-Throughput Screening Assays; Humans; Hydrophobic and Hydrophilic Interactions; Ligands; Molecular Targeted Therapy; Proteasome Endopeptidase Complex; Protein Binding; Protein Processing, Post-Translational; Protein Unfolding; Proteolysis; Proteomics; Proteostasis; Small Molecule Libraries; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 33632029
DOI: 10.1177/2472555221991104 -
Trends in Biotechnology Apr 2014Due to their unlimited chemical diversity, small molecules can rival monoclonal antibodies (mAbs) with respect to specificity and affinity for target molecules. However,... (Review)
Review
Due to their unlimited chemical diversity, small molecules can rival monoclonal antibodies (mAbs) with respect to specificity and affinity for target molecules. However, key pharmacological properties of mAbs remain unmatched by small molecules. Chemical programming strategies have been developed for site-specific and covalent conjugation of small molecules to mAbs with unique reactivity centers. In addition to blending favorable features of small molecules and mAbs, chemically programmed antibodies (cpAbs) are economically attractive because they utilize the same mAb for an almost unlimited number of target molecule specificities, reducing manufacturing costs and shortening drug discovery and development time. Preclinical studies and clinical trials have begun to demonstrate the broad utility of cpAbs for the treatment and prevention of human diseases.
Topics: Antibodies; Antibodies, Monoclonal; Binding Sites; Biotechnology; Protein Engineering
PubMed: 24630478
DOI: 10.1016/j.tibtech.2014.02.003 -
Acta Pharmaceutica Sinica. B Dec 2022Immunotherapy has led to a paradigm shift in the treatment of cancer. Current cancer immunotherapies are mostly antibody-based, thus possessing advantages in regard to... (Review)
Review
Immunotherapy has led to a paradigm shift in the treatment of cancer. Current cancer immunotherapies are mostly antibody-based, thus possessing advantages in regard to pharmacodynamics (., specificity and efficacy). However, they have limitations in terms of pharmacokinetics including long half-lives, poor tissue/tumor penetration, and little/no oral bioavailability. In addition, therapeutic antibodies are immunogenic, thus may cause unwanted adverse effects. Therefore, researchers have shifted their efforts towards the development of small molecule-based cancer immunotherapy, as small molecules may overcome the above disadvantages associated with antibodies. Further, small molecule-based immunomodulators and therapeutic antibodies are complementary modalities for cancer treatment, and may be combined to elicit synergistic effects. Recent years have witnessed the rapid development of small molecule-based cancer immunotherapy. In this review, we describe the current progress in small molecule-based immunomodulators (inhibitors/agonists/degraders) for cancer therapy, including those targeting PD-1/PD-L1, chemokine receptors, stimulator of interferon genes (STING), Toll-like receptor (TLR), etc. The tumorigenesis mechanism of various targets and their respective modulators that have entered clinical trials are also summarized.
PubMed: 36562003
DOI: 10.1016/j.apsb.2022.11.007 -
Cell Chemical Biology Mar 2021Profiling approaches such as gene expression or proteome profiling generate small-molecule bioactivity profiles that describe a perturbed cellular state in a rather... (Review)
Review
Profiling approaches such as gene expression or proteome profiling generate small-molecule bioactivity profiles that describe a perturbed cellular state in a rather unbiased manner and have become indispensable tools in the evaluation of bioactive small molecules. Automated imaging and image analysis can record morphological alterations that are induced by small molecules through the detection of hundreds of morphological features in high-throughput experiments. Thus, morphological profiling has gained growing attention in academia and the pharmaceutical industry as it enables detection of bioactivity in compound collections in a broader biological context in the early stages of compound development and the drug-discovery process. Profiling may be used successfully to predict mode of action or targets of unexplored compounds and to uncover unanticipated activity for already characterized small molecules. Here, we review the reported approaches to morphological profiling and the kind of bioactivity that can be detected so far and, thus, predicted.
Topics: Drug Discovery; Drug Industry; High-Throughput Screening Assays; Humans; Small Molecule Libraries
PubMed: 33740434
DOI: 10.1016/j.chembiol.2021.02.012 -
Frontiers in Bioengineering and... 2022The comprehensive reconstruction of extensive craniofacial and dentoalveolar defects remains a major clinical challenge to this day, especially in complex medical cases... (Review)
Review
The comprehensive reconstruction of extensive craniofacial and dentoalveolar defects remains a major clinical challenge to this day, especially in complex medical cases involving cancer, cranioplasty, and traumatic injury. Currently, osteogenic small molecule-based compounds have been explored extensively to repair and regenerate bone tissue because of their unique advantages. Over the past few years, a number of small molecules with the potential of craniofacial and periodontal bone tissue regeneration have been reported in literature. In this review, we discuss current progress using small molecules to regulate cranial and periodontal bone regeneration. Future directions of craniofacial bone regenerative engineering using the small molecule-based compounds will be discussed as well.
PubMed: 36406208
DOI: 10.3389/fbioe.2022.1003936