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Molecules (Basel, Switzerland) Jul 2022Molecular docking plays a significant role in early-stage drug discovery, from structure-based virtual screening (VS) to hit-to-lead optimization, and its capability and... (Review)
Review
Molecular docking plays a significant role in early-stage drug discovery, from structure-based virtual screening (VS) to hit-to-lead optimization, and its capability and predictive power is critically dependent on the protein-ligand scoring function. In this review, we give a broad overview of recent scoring function development, as well as the docking-based applications in drug discovery. We outline the strategies and resources available for structure-based VS and discuss the assessment and development of classical and machine learning protein-ligand scoring functions. In particular, we highlight the recent progress of machine learning scoring function ranging from descriptor-based models to deep learning approaches. We also discuss the general workflow and docking protocols of structure-based VS, such as structure preparation, binding site detection, docking strategies, and post-docking filter/re-scoring, as well as a case study on the large-scale docking-based VS test on the LIT-PCBA data set.
Topics: Ligands; Machine Learning; Molecular Docking Simulation; Protein Binding; Proteins
PubMed: 35889440
DOI: 10.3390/molecules27144568 -
Molecules (Basel, Switzerland) Jan 2021Reactions of cyclometalated compounds are numerous. This account is focused on one of such reactions, the exchange of cyclometalated ligands, a reaction between a... (Review)
Review
Reactions of cyclometalated compounds are numerous. This account is focused on one of such reactions, the exchange of cyclometalated ligands, a reaction between a cyclometalated compound and an incoming ligand that replaces a previously cyclometalated ligand to form a new metalacycle: + H-C*~Z ⇄ + H-C~Y. Originally discovered for Pd complexes with Y/Z = N, P, S, the exchange appeared to be a mechanistically challenging, simple, and convenient routine for the synthesis of cyclopalladated complexes. Over four decades it was expanded to cyclometalated derivatives of platinum, ruthenium, manganese, rhodium, and iridium. The exchange, which is also questionably referred to as transcyclometalation, offers attractive synthetic possibilities and assists in disclosing key mechanistic pathways associated with the C-H bond activation by transition metal complexes and C-M bond cleavage. Both synthetic and mechanistic aspects of the exchange are reviewed and discussed.
Topics: Ligands; Metals; Molecular Structure; Organometallic Compounds
PubMed: 33401624
DOI: 10.3390/molecules26010210 -
Bioinformatics (Oxford, England) Feb 2020The use of experimental information has been demonstrated to increase the success rate of computational macromolecular docking. Many methods use information to...
MOTIVATION
The use of experimental information has been demonstrated to increase the success rate of computational macromolecular docking. Many methods use information to post-filter the simulation output while others drive the simulation based on experimental restraints, which can become problematic for more complex scenarios such as multiple binding interfaces.
RESULTS
We present a novel method for including interface information into protein docking simulations within the LightDock framework. Prior to the simulation, irrelevant regions from the receptor are excluded for sampling (filter of initial swarms) and initial ligand poses are pre-oriented based on ligand input information. We demonstrate the applicability of this approach on the new 55 cases of the Protein-Protein Docking Benchmark 5, using different amounts of information. Even with incomplete or incorrect information, a significant improvement in performance is obtained compared to blind ab initio docking.
AVAILABILITY AND IMPLEMENTATION
The software is supported and freely available from https://github.com/brianjimenez/lightdock and analysis data from https://github.com/brianjimenez/lightdock_bm5.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Computational Biology; Ligands; Proteins; Software
PubMed: 31418773
DOI: 10.1093/bioinformatics/btz642 -
Current Opinion in Structural Biology Feb 2022In standard crystallographic refinement of biomacromolecules, the crystallographic raw data are supplemented by empirical restraints that ensure that the structure makes... (Review)
Review
In standard crystallographic refinement of biomacromolecules, the crystallographic raw data are supplemented by empirical restraints that ensure that the structure makes chemical sense. These restraints are typically accurate for amino acids and nucleic acids, but less so for cofactors, substrates, inhibitors, ligands and metal sites. In quantum refinement, this potential is replaced by more accurate quantum mechanical (QM) calculations. Several implementations have been presented, differing in the level of QM and whether it is used for the entire structure or only for a site of particular interest. It has been shown that the method can improve and correct errors in crystal structures and that it can be used to determine protonation and tautomeric states of various ligands and to decide what is really seen in the structure by refining different interpretations and using standard crystallographic and QM quality measures to decide which fits the structure best.
Topics: Crystallography, X-Ray; Ligands; Models, Molecular; Quantum Theory
PubMed: 34392061
DOI: 10.1016/j.sbi.2021.07.002 -
International Journal of Molecular... May 2023Gaining insight into the in situ receptor-ligand binding is pivotal for revealing the molecular mechanisms underlying the physiological and pathological processes and... (Review)
Review
Gaining insight into the in situ receptor-ligand binding is pivotal for revealing the molecular mechanisms underlying the physiological and pathological processes and will contribute to drug discovery and biomedical application. An important issue involved is how the receptor-ligand binding responds to mechanical stimuli. This review aims to provide an overview of the current understanding of the effect of several representative mechanical factors, such as tension, shear stress, stretch, compression, and substrate stiffness on receptor-ligand binding, wherein the biomedical implications are focused. In addition, we highlight the importance of synergistic development of experimental and computational methods for fully understanding the in situ receptor-ligand binding, and further studies should focus on the coupling effects of these mechanical factors.
Topics: Mechanotransduction, Cellular; Ligands; Stress, Mechanical; Pressure
PubMed: 37240408
DOI: 10.3390/ijms24109062 -
The Journal of Physical Chemistry. B Apr 2019Many instances of cellular signaling and transcriptional regulation involve switch-like molecular responses to the presence or absence of input ligands. To understand...
Many instances of cellular signaling and transcriptional regulation involve switch-like molecular responses to the presence or absence of input ligands. To understand how these responses come about and how they can be harnessed, we develop a statistical mechanical model to characterize the types of Boolean logic that can arise from allosteric molecules following the Monod-Wyman-Changeux (MWC) model. Building upon previous work, we show how an allosteric molecule regulated by two inputs can elicit AND, OR, NAND, and NOR responses but is unable to realize XOR or XNOR gates. Next, we demonstrate the ability of an MWC molecule to perform ratiometric sensing-a response behavior where activity depends monotonically on the ratio of ligand concentrations. We then extend our analysis to more general schemes of combinatorial control involving either additional binding sites for the two ligands or an additional third ligand and show how these additions can cause a switch in the logic behavior of the molecule. Overall, our results demonstrate the wide variety of control schemes that biological systems can implement using simple mechanisms.
Topics: Allosteric Regulation; Ligands; Models, Biological
PubMed: 30768906
DOI: 10.1021/acs.jpcb.8b12517 -
Frontiers in Endocrinology 2023Gonadotropins regulate reproductive functions by binding to G protein-coupled receptors (FSHR and LHCGR) expressed in the gonads. They activate multiple, cell-specific... (Review)
Review
Gonadotropins regulate reproductive functions by binding to G protein-coupled receptors (FSHR and LHCGR) expressed in the gonads. They activate multiple, cell-specific signalling pathways, consisting of ligand-dependent intracellular events. Signalling cascades may be modulated by synthetic compounds which bind allosteric sites of FSHR and LHCGR or by membrane receptor interactions. Despite the hormone binding to the orthosteric site, allosteric ligands, and receptor heteromerizations may reshape intracellular signalling pattern. These molecules act as positive, negative, or neutral allosteric modulators, as well as non-competitive or inverse agonist ligands, providing a set of new compounds of a different nature and with unique pharmacological characteristics. Gonadotropin receptor allosteric modulation is gathering increasing interest from the scientific community and may be potentially exploited for clinical purposes. This review summarizes the current knowledge on gonadotropin receptor allosteric modulation and their potential, clinical use.
Topics: Drug Inverse Agonism; Ligands; Receptors, Gonadotropin; Signal Transduction; Gonads
PubMed: 37305033
DOI: 10.3389/fendo.2023.1179079 -
Methods in Cell Biology 2021We compare the GPCR-ligand interactions and highlight important residues for recognition in purinergic receptors-from both X-ray crystallographic and cryo-EM structures.... (Review)
Review
We compare the GPCR-ligand interactions and highlight important residues for recognition in purinergic receptors-from both X-ray crystallographic and cryo-EM structures. These include A and A adenosine receptors, and P2Y and P2Y receptors that respond to ADP and other nucleotides. These receptors are important drug discovery targets for immune, metabolic and nervous system disorders. In most cases, orthosteric ligands are represented, except for one allosteric P2Y antagonist. This review catalogs the residues and regions that engage in contacts with ligands or with other GPCR protomers in dimeric forms. Residues that are in proximity to bound ligands within purinergic GPCR families are correlated. There is extensive conservation of recognition motifs between adenosine receptors, but the P2Y and P2Y receptors are each structurally distinct in their ligand recognition. Identifying common interaction features for ligand recognition within a receptor class that has multiple structures available can aid in the drug discovery process.
Topics: Dimerization; Drug Discovery; Humans; Ligands
PubMed: 34752329
DOI: 10.1016/bs.mcb.2021.06.001 -
Current Opinion in Biotechnology Aug 2021Plants have the ability to detect and respond to biotic stresses. They contain pattern recognition receptors (PRRs) that specifically recognize conserved molecules from... (Review)
Review
Plants have the ability to detect and respond to biotic stresses. They contain pattern recognition receptors (PRRs) that specifically recognize conserved molecules from their enemies and activate immune responses. In this review, I discuss recent efforts to discover PRRs for herbivory-associated cues that originate from oral secretions, eggs, damaged plant cells or secondary endogenous signals. Although several potential PRRs have been identified and shown to confer resistance to insects, proof of direct binding to a ligand is scarce and there are still many uncharacterized ligand-receptor pairs. However, several studies suggest that, like for microbial pathogens, plants use similar PRR complexes to detect herbivory.
Topics: Herbivory; Ligands; Plant Immunity; Plants; Receptors, Pattern Recognition
PubMed: 34023544
DOI: 10.1016/j.copbio.2021.04.004 -
Bioscience Reports Feb 2024Aging brings about a myriad of degenerative processes throughout the body. A decrease in cognitive abilities is one of the hallmark phenotypes of aging, underpinned by... (Review)
Review
Aging brings about a myriad of degenerative processes throughout the body. A decrease in cognitive abilities is one of the hallmark phenotypes of aging, underpinned by neuroinflammation and neurodegeneration occurring in the brain. This review focuses on the role of different immune receptors expressed in cells of the central and peripheral nervous systems. We will discuss how immune receptors in the brain act as sentinels and effectors of the age-dependent shift in ligand composition. Within this 'old-age-ligand soup,' some immune receptors contribute directly to excessive synaptic weakening from within the neuronal compartment, while others amplify the damaging inflammatory environment in the brain. Ultimately, chronic inflammation sets up a positive feedback loop that increases the impact of immune ligand-receptor interactions in the brain, leading to permanent synaptic and neuronal loss.
Topics: Humans; Ligands; Brain; Aging; Inflammation; Cognition
PubMed: 38299364
DOI: 10.1042/BSR20222267