-
Journal of Chemical Information and... Dec 2023The Automated Ligand Searcher (ALISE) is designed as an automated computational drug discovery tool. To approximate the binding free energy of ligands to a receptor,...
The Automated Ligand Searcher (ALISE) is designed as an automated computational drug discovery tool. To approximate the binding free energy of ligands to a receptor, ALISE includes a three-stage workflow, with each stage involving an increasingly sophisticated computational method: molecular docking, molecular dynamics, and free energy perturbation, respectively. To narrow the number of potential ligands, poorly performing ligands are gradually segregated out. The performance and usability of ALISE are benchmarked for a case study containing known active ligands and decoys for the HIV protease. The example illustrates that ALISE filters the decoys successfully and demonstrates that the automation, comprehensiveness, and user-friendliness of the software make it a valuable tool for improved and faster drug development workflows.
Topics: Ligands; Molecular Docking Simulation; Software; Molecular Dynamics Simulation; Drug Discovery; Protein Binding
PubMed: 37983165
DOI: 10.1021/acs.jcim.3c01317 -
British Journal of Pharmacology Oct 2023The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format,... (Review)
Review
The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16176. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Topics: Humans; Databases, Pharmaceutical; Ion Channels; Ligands; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled
PubMed: 38123154
DOI: 10.1111/bph.16181 -
International Journal of Molecular... Jan 2024The mannose receptor (MR, CD 206) is an endocytic receptor primarily expressed by macrophages and dendritic cells, which plays a critical role in both endocytosis and... (Review)
Review
The mannose receptor (MR, CD 206) is an endocytic receptor primarily expressed by macrophages and dendritic cells, which plays a critical role in both endocytosis and antigen processing and presentation. MR carbohydrate recognition domains (CRDs) exhibit a high binding affinity for branched and linear oligosaccharides. Furthermore, multivalent mannose presentation on the various templates like peptides, proteins, polymers, micelles, and dendrimers was proven to be a valuable approach for the selective and efficient delivery of various therapeutically active agents to MR. This review provides a detailed account of the most relevant and recent aspects of the synthesis and application of mannosylated bioactive formulations for MR-mediated delivery in treatments of cancer and other infectious diseases. It further highlights recent findings related to the necessary structural features of the mannose-containing ligands for successful binding to the MR.
Topics: Mannose Receptor; Mannose; Receptors, Cell Surface; Mannose-Binding Lectins; Lectins, C-Type; Ligands
PubMed: 38338648
DOI: 10.3390/ijms25031370 -
Annual Review of Cell and Developmental... Oct 2023Cell-cell communication is critical for the development and function of multicellular organisms. A crucial means by which cells communicate with one another is physical... (Review)
Review
Cell-cell communication is critical for the development and function of multicellular organisms. A crucial means by which cells communicate with one another is physical interactions between receptors on one cell and their ligands on a neighboring cell. ligand:receptor interactions activate the receptor, ultimately leading to changes in the fate of the receptor-expressing cells. Such signaling is known to be critical for the functions of cells in the nervous and immune systems, among others. Historically, interactions are the primary conceptual framework for understanding cell-cell communication. However, cells often coexpress many receptors and ligands, and a subset of these has been reported to interact in and profoundly impact cell functions. interactions likely constitute a fundamental, understudied regulatory mechanism in cell biology. Here, I discuss how interactions between membrane receptors and ligands regulate immune cell functions, and I also highlight outstanding questions in the field.
Topics: Ligands; Cell Communication; Signal Transduction
PubMed: 37339682
DOI: 10.1146/annurev-cellbio-120420-103941 -
Journal of Chemical Theory and... Nov 2023Modern therapeutic development often involves several stages that are interconnected, and multiple iterations are usually required to bring a new drug to the market.... (Review)
Review
Modern therapeutic development often involves several stages that are interconnected, and multiple iterations are usually required to bring a new drug to the market. Computational approaches have increasingly become an indispensable part of helping reduce the time and cost of the research and development of new drugs. In this Perspective, we summarize our recent efforts on integrating molecular modeling and machine learning to develop computational tools for modulator design, including a pocket-guided rational design approach based on AlphaSpace to target protein-protein interactions, delta machine learning scoring functions for protein-ligand docking as well as virtual screening, and state-of-the-art deep learning models to predict calculated and experimental molecular properties based on molecular mechanics optimized geometries. Meanwhile, we discuss remaining challenges and promising directions for further development and use a retrospective example of FDA approved kinase inhibitor Erlotinib to demonstrate the use of these newly developed computational tools.
Topics: Retrospective Studies; Molecular Docking Simulation; Machine Learning; Drug Design; Proteins; Ligands
PubMed: 37883810
DOI: 10.1021/acs.jctc.3c00814 -
Bioorganic & Medicinal Chemistry Jun 2023Over the last two decades, proteolysis targeting chimeras (PROTACs) have been revolutionary in drug development rendering targeted protein degradation (TPD) as an... (Review)
Review
Over the last two decades, proteolysis targeting chimeras (PROTACs) have been revolutionary in drug development rendering targeted protein degradation (TPD) as an emerging therapeutic modality. These heterobifunctional molecules are comprised of three units: a ligand for the protein of interest (POI), a ligand for an E3 ubiquitin ligase, and a linker that tethers the two motifs together. Von Hippel-Lindau (VHL) is one of the most widely employed E3 ligases in PROTACs development due to its prevalent expression across tissue types and well-characterised ligands. Linker composition and length has proven to play an important role in determining the physicochemical properties and spatial orientation of the POI-PROTAC-E3 ternary complex, thus influencing the bioactivity of degraders. Numerous articles and reports have been published showcasing the medicinal chemistry aspects of the linker design, but few have focused on the chemistry around tethering linkers to E3 ligase ligands. In this review, we focus on the current synthetic linker strategies employed in the assembly of VHL-recruiting PROTACs. We aim to cover a range of fundamental chemistries used to incorporate linkers of varying length, composition and functionality.
Topics: Ligands; Proteins; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 37224698
DOI: 10.1016/j.bmc.2023.117334 -
Nature Neuroscience Aug 2023Extrinsic signaling between diverse cell types is crucial for nervous system development. Ligand binding is a key driver of developmental processes. Nevertheless, it...
Extrinsic signaling between diverse cell types is crucial for nervous system development. Ligand binding is a key driver of developmental processes. Nevertheless, it remains a significant challenge to disentangle which and how extrinsic signals act cooperatively to affect changes in recipient cells. In the developing human brain, cortical progenitors transition from neurogenesis to gliogenesis in a stereotyped sequence that is in part influenced by extrinsic ligands. Here we used published transcriptomic data to identify and functionally test five ligand-receptor pairs that synergistically drive human astrogenesis. We validate the synergistic contributions of TGFβ2, NLGN1, TSLP, DKK1 and BMP4 ligands on astrocyte development in both hCOs and primary fetal tissue. We confirm that the cooperative capabilities of these five ligands are greater than their individual capacities. Additionally, we discovered that their combinatorial effects converge in part on the mTORC1 signaling pathway, resulting in transcriptomic and morphological features of astrocyte development. Our data-driven framework can leverage single-cell and bulk genomic data to generate and test functional hypotheses surrounding cell-cell communication regulating neurodevelopmental processes.
Topics: Humans; Astrocytes; Ligands; Neurogenesis; Signal Transduction; Brain
PubMed: 37460808
DOI: 10.1038/s41593-023-01375-8 -
European Journal of Medicinal Chemistry Dec 2023Perforin is a pore-forming protein whose normal function enables cytotoxic T and natural killer (NK) cells to kill virus-infected and transformed cells. Conversely,...
Perforin is a pore-forming protein whose normal function enables cytotoxic T and natural killer (NK) cells to kill virus-infected and transformed cells. Conversely, unwanted perforin activity can also result in auto-immune attack, graft rejection and aberrant responses to pathogens. Perforin is critical for the function of the granule exocytosis cell death pathway and is therefore a target for drug development. In this study, by screening a fragment library using NMR and surface plasmon resonance, we identified 4,4-diaminodiphenyl sulfone (dapsone) as a perforin ligand. We also found that dapsone has modest (mM) inhibitory activity of perforin lytic activity in a red blood cell lysis assay in vitro. Sequential modification of this lead fragment, guided by structural knowledge of the ligand binding site and binding pose, and supported by SPR and ligand-detected F NMR, enabled the design of nanomolar inhibitors of the cytolytic activity of intact NK cells against various tumour cell targets. Interestingly, the ligands we developed were largely inert with respect to direct perforin-mediated red blood cell lysis but were very potent in the context of perforin's action on delivering granzymes in the immune synapse, the context in which it functions physiologically. Our work indicates that a fragment-based, structure-guided drug discovery strategy can be used to identify novel ligands that bind perforin. Moreover, these molecules have superior physicochemical properties and solubility compared to previous generations of perforin ligands.
Topics: Perforin; Ligands; Killer Cells, Natural; Cell Death; Dapsone
PubMed: 37716187
DOI: 10.1016/j.ejmech.2023.115786 -
Cell Reports Mar 2024Prostaglandin F (PGF) and thromboxane A (TXA) are endogenous arachidonic acid metabolites, modulating diverse physiological processes including inflammation and...
Prostaglandin F (PGF) and thromboxane A (TXA) are endogenous arachidonic acid metabolites, modulating diverse physiological processes including inflammation and cardiovascular homeostasis through activating PGF receptor (FP) and TXA receptor (TP). Ligands targeting FP and TP have demonstrated efficacy in treating conditions like glaucoma and cardiovascular diseases in humans, as well as reproductive-related diseases in animals. Here, we present five cryoelectron microscopy structures illustrating FP and TP in complex with G and bound to PGF (endogenous ligand), latanoprost acid (a clinical drug), and two other synthetic agonists. Combined with mutational and functional studies, these structures reveal not only structural features for the specific recognition of endogenous ligands and attainment of receptor selectivity of FP and TP but also the common mechanisms of receptor activation and G protein coupling. The findings may enrich our knowledge of ligand recognition and signal transduction of the prostanoid receptor family and facilitate rational ligand design toward these two receptors.
Topics: Humans; Animals; Ligands; Cryoelectron Microscopy; Receptors, Prostaglandin; Signal Transduction; Prostaglandins
PubMed: 38446662
DOI: 10.1016/j.celrep.2024.113893 -
Bioinformatics (Oxford, England) Jul 2023Identifying the probable positions of the protein side-chains is one of the protein modelling steps that can improve the prediction of protein-ligand and protein-protein...
MOTIVATION
Identifying the probable positions of the protein side-chains is one of the protein modelling steps that can improve the prediction of protein-ligand and protein-protein interactions. Most of the strategies predicting the side-chain conformations use predetermined dihedral angle lists, also called rotamer libraries, that are usually generated from a subset of high-quality protein structures. Although these methods are fast to apply, they tend to average out geometries instead of taking into account the surrounding atoms and molecules and ignore structures not included in the selected subset. Such simplifications can result in inaccuracies when predicting possible side-chain atom positions.
RESULTS
We propose an approach that takes into account both of these circumstances by scanning through sterically accessible side-chain conformations and generating dihedral angle libraries specific to the target proteins. The method avoids the drawbacks of lacking conformations due to unusual or rare protein structures and successfully suggests potential rotamers with average RMSD closer to the experimentally determined side-chain atom positions than other widely used rotamer libraries.
AVAILABILITY AND IMPLEMENTATION
The technique is implemented in open-source software package rotag and available at GitHub: https://www.github.com/agrybauskas/rotag, under GNU Lesser General Public License.
Topics: Models, Molecular; Proteins; Molecular Conformation; Software; Ligands; Protein Conformation
PubMed: 37439702
DOI: 10.1093/bioinformatics/btad429