scholarly journals Substrate binding modes of purine and pyrimidine nucleotides to human ecto-5′-nucleotidase (CD73) and inhibition by their bisphosphonic acid derivatives

2021 ◽  
Author(s):  
Emma Scaletti ◽  
Franziska U. Huschmann ◽  
Uwe Mueller ◽  
Manfred S. Weiss ◽  
Norbert Sträter
Keyword(s):  
Control Point ◽  
Initial Step ◽  
Binding Mode ◽  
Purinergic Signalling ◽  
Binding Modes ◽  
Pyrimidine Nucleotides ◽  
Diverse Range ◽  
Bisphosphonic Acid ◽  
Fragment Screening ◽  
Immunosuppressive Action

AbstractHuman ecto-5-nucleotidase (CD73) is involved in purinergic signalling, which influences a diverse range of biological processes. CD73 hydrolyses AMP and is the major control point for the levels of extracellular adenosine. Inhibitors of CD73 thus block the immunosuppressive action of adenosine, a promising approach for cancer immunotherapy. Interestingly, ADP and ATP are competitive inhibitors of CD73, with the most potent small-molecule inhibitors to date being non-hydrolysable ADP analogues. While AMP is the major substrate of the enzyme, CD73 has been reported to hydrolyse other 5′-nucleoside monophosphates. Based on a fragment screening campaign at the BESSY II synchrotron, we present the binding modes of various deoxyribo- and ribonucleoside monophosphates and of four additional fragments binding to the nucleoside binding site of the open form of the enzyme. Kinetic analysis of monophosphate hydrolysis shows that ribonucleotide substrates are favoured over their deoxyribose equivalents with AMP being the best substrate. We characterised the initial step of AMP hydrolysis, the binding mode of AMP to the open conformation of CD73 and compared that to other monophosphate substrates. In addition, the inhibitory activity of various bisphosphonic acid derivatives of nucleoside diphosphates was determined. Although AMPCP remains the most potent inhibitor, replacement of the adenine base with other purines or with pyrimidines increases the Ki value only between twofold and sixfold. On the other hand, these nucleobases offer new opportunities to attach substituents for improved pharmacological properties.

scholarly journals Complexed Crystal Structure of Saccharomyces cerevisiae Dihydroorotase with Inhibitor 5-Fluoroorotate Reveals a New Binding Mode

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Hong-Hsiang Guan ◽  
Yen-Hua Huang ◽  
En-Shyh Lin ◽  
Chun-Jung Chen ◽  
Cheng-Yang Huang
Keyword(s):  
Crystal Structure ◽  
Saccharomyces Cerevisiae ◽  
Active Site ◽  
Structural Similarity ◽  
Binding Mode ◽  
Site Directed Mutagenesis ◽  
Molecular Evidence ◽  
Binding Modes ◽  
Pyrimidine Nucleotides ◽  
Quenching Method

Dihydroorotase (DHOase) possesses a binuclear metal center in which two Zn ions are bridged by a posttranslationally carbamylated lysine. DHOase catalyzes the reversible cyclization of N-carbamoyl aspartate (CA-asp) to dihydroorotate (DHO) in the third step of the pathway for the biosynthesis of pyrimidine nucleotides and is an attractive target for potential anticancer and antimalarial chemotherapy. Crystal structures of ligand-bound DHOase show that the flexible loop extends toward the active site when CA-asp is bound (loop-in mode) or moves away from the active site, facilitating the product DHO release (loop-out mode). DHOase binds the product-like inhibitor 5-fluoroorotate (5-FOA) in a similar mode to DHO. In the present study, we report the crystal structure of DHOase from Saccharomyces cerevisiae (ScDHOase) complexed with 5-FOA at 2.5 Å resolution (PDB entry 7CA0). ScDHOase shares structural similarity with Escherichia coli DHOase (EcDHOase). However, our complexed structure revealed that ScDHOase bound 5-FOA differently from EcDHOase. 5-FOA ligated the Zn atoms in the active site of ScDHOase. In addition, 5-FOA bound to ScDHOase through the loop-in mode. We also characterized the binding of 5-FOA to ScDHOase by using the site-directed mutagenesis and fluorescence quenching method. Based on these lines of molecular evidence, we discussed whether these different binding modes are species- or crystallography-dependent.

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

2017 ◽  
Author(s):  
Samuel Gill ◽  
Nathan M. Lim ◽  
Patrick Grinaway ◽  
Ariën S. Rustenburg ◽  
Josh Fass ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Enhanced Sampling ◽  
Recent Success ◽  
Multiple Binding ◽  
Proper Sampling

<div>Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes.</div><div><br></div><div>In this technique the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.</div>

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

2018 ◽  
Author(s):  
Samuel Gill ◽  
Nathan M. Lim ◽  
Patrick Grinaway ◽  
Ariën S. Rustenburg ◽  
Josh Fass ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Enhanced Sampling ◽  
Recent Success ◽  
Multiple Binding ◽  
Proper Sampling

<div>Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes.</div><div><br></div><div>In this technique the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.</div>

scholarly journals Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 686 ◽  
Author(s):  
Alexander Neumann ◽  
Viktor Engel ◽  
Andhika B. Mahardhika ◽  
Clara T. Schoeder ◽  
Vigneshwaran Namasivayam ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
G Protein ◽  
Phenyl Ring ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Binding Modes ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target.

scholarly journals Spanning the gap: unraveling RSC dynamics in vivo

2021 ◽  
Author(s):  
Heinz Neumann ◽  
Bryan J. Wilkins
Keyword(s):  
Cell Cycle ◽  
Posttranslational Modifications ◽  
Transcriptional Activation ◽  
Binding Mode ◽  
Binding Modes ◽  
Binding Domains ◽  
Binding Interface ◽  
The Many ◽  
And Function

AbstractMultiple reports over the past 2 years have provided the first complete structural analyses for the essential yeast chromatin remodeler, RSC, providing elaborate molecular details for its engagement with the nucleosome. However, there still remain gaps in resolution, particularly within the many RSC subunits that harbor histone binding domains.Solving contacts at these interfaces is crucial because they are regulated by posttranslational modifications that control remodeler binding modes and function. Modifications are dynamic in nature often corresponding to transcriptional activation states and cell cycle stage, highlighting not only a need for enriched spatial resolution but also temporal understanding of remodeler engagement with the nucleosome. Our recent work sheds light on some of those gaps by exploring the binding interface between the RSC catalytic motor protein, Sth1, and the nucleosome, in the living nucleus. Using genetically encoded photo-activatable amino acids incorporated into histones of living yeast we are able to monitor the nucleosomal binding of RSC, emphasizing the regulatory roles of histone modifications in a spatiotemporal manner. We observe that RSC prefers to bind H2B SUMOylated nucleosomes in vivo and interacts with neighboring nucleosomes via H3K14ac. Additionally, we establish that RSC is constitutively bound to the nucleosome and is not ejected during mitotic chromatin compaction but alters its binding mode as it progresses through the cell cycle. Our data offer a renewed perspective on RSC mechanics under true physiological conditions.

scholarly journals SuCOS is Better than RMSD for Evaluating Fragment Elaboration and Docking Poses

2019 ◽  
Author(s):  
Susan Leung ◽  
Michael Bodkin ◽  
Frank von Delft ◽  
Paul Brennan ◽  
Garrett Morris
Keyword(s):  
Binding Mode ◽  
Docking Studies ◽  
Binding Modes ◽  
False Negatives ◽  
Ligand Interaction ◽  
Cross Docking ◽  
Protein Ligand Interaction ◽  
Feature Overlap ◽  
Better Than ◽  
Fragment Based Drug Discovery

One of the fundamental assumptions of fragment-based drug discovery is that the fragment’s binding mode will be conserved upon elaboration into larger compounds. The most common way of quantifying binding mode similarity is Root Mean Square Deviation (RMSD), but Protein Ligand Interaction Fingerprint (PLIF) similarity and shape-based metrics are sometimes used. We introduce SuCOS, an open-source shape and chemical feature overlap metric. We explore the strengths and weaknesses of RMSD, PLIF similarity, and SuCOS on a dataset of X-ray crystal structures of paired elaborated larger and smaller molecules bound to the same protein. Our redocking and cross-docking studies show that SuCOS is superior to RMSD and PLIF similarity. When redocking, SuCOS produces fewer false positives and false negatives than RMSD and PLIF similarity; and in cross-docking, SuCOS is better at differentiating experimentally-observed binding modes of an elaborated molecule given the pose of its non-elaborated counterpart. Finally we show that SuCOS performs better than AutoDock Vina at differentiating actives from decoy ligands using the DUD-E dataset. SuCOS is available at https://github.com/susanhleung/SuCOS . <br>

scholarly journals Dissimilar Ligands Bind in a Similar Fashion: A Guide to Ligand Binding-Mode Prediction with Application to CELPP Studies

2021 ◽  
Vol 22 (22) ◽  
pp. 12320
Author(s):  
Xianjin Xu ◽  
Xiaoqin Zou
Keyword(s):  
Molecular Similarity ◽  
Complex Structure ◽  
Binding Mode ◽  
Molecular Structures ◽  
Complex Structures ◽  
Binding Modes ◽  
Ligand Complex ◽  
Systematic Analysis ◽  
Binding Mode Prediction ◽  
Similarity Principle

The molecular similarity principle has achieved great successes in the field of drug design/discovery. Existing studies have focused on similar ligands, while the behaviors of dissimilar ligands remain unknown. In this study, we developed an intercomparison strategy in order to compare the binding modes of ligands with different molecular structures. A systematic analysis of a newly constructed protein–ligand complex structure dataset showed that ligands with similar structures tended to share a similar binding mode, which is consistent with the Molecular Similarity Principle. More importantly, the results revealed that dissimilar ligands can also bind in a similar fashion. This finding may open another avenue for drug discovery. Furthermore, a template-guiding method was introduced for predicting protein–ligand complex structures. With the use of dissimilar ligands as templates, our method significantly outperformed the traditional molecular docking methods. The newly developed template-guiding method was further applied to recent CELPP studies.

scholarly journals SuCOS is Better than RMSD for Evaluating Fragment Elaboration and Docking Poses

2019 ◽  
Author(s):  
Susan Leung ◽  
Michael Bodkin ◽  
Frank von Delft ◽  
Paul Brennan ◽  
Garrett Morris
Keyword(s):  
Binding Mode ◽  
Docking Studies ◽  
Binding Modes ◽  
False Negatives ◽  
Ligand Interaction ◽  
Cross Docking ◽  
Protein Ligand Interaction ◽  
Feature Overlap ◽  
Better Than ◽  
Fragment Based Drug Discovery

One of the fundamental assumptions of fragment-based drug discovery is that the fragment’s binding mode will be conserved upon elaboration into larger compounds. The most common way of quantifying binding mode similarity is Root Mean Square Deviation (RMSD), but Protein Ligand Interaction Fingerprint (PLIF) similarity and shape-based metrics are sometimes used. We introduce SuCOS, an open-source shape and chemical feature overlap metric. We explore the strengths and weaknesses of RMSD, PLIF similarity, and SuCOS on a dataset of X-ray crystal structures of paired elaborated larger and smaller molecules bound to the same protein. Our redocking and cross-docking studies show that SuCOS is superior to RMSD and PLIF similarity. When redocking, SuCOS produces fewer false positives and false negatives than RMSD and PLIF similarity; and in cross-docking, SuCOS is better at differentiating experimentally-observed binding modes of an elaborated molecule given the pose of its non-elaborated counterpart. Finally we show that SuCOS performs better than AutoDock Vina at differentiating actives from decoy ligands using the DUD-E dataset. SuCOS is available at https://github.com/susanhleung/SuCOS . <br>

Design, Synthesis, Molecular Docking and Biological Studies of New Heterocyclic Compounds Derived from -Diketonesas Novel EGFR and Pim-1 Inhibitors Endowed with Antitumor Activity

2022 ◽  
Vol 22 ◽  
Author(s):  
Rafat Milad Mohareb ◽  
Noha M. Asaad Bagato ◽  
Ibrahim Taha Radwan
Keyword(s):  
Molecular Docking ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Diethyl Malonate ◽  
Binding Mode ◽  
Binding Modes ◽  
Binding Interactions ◽  
Biological Studies

Background: Cancer is a disease illustrated by a shift in the controlled mechanisms that control both cell proliferation and differentiation. It is regarded as a prime health problem worldwide, leading cause of human death-rate exceeded only by cardiovascular diseases. Many reported work was concerned with the discovery of new antitumor compounds this encourage us to synthesis new anticancer agents. Objective: In this work, we are aiming to synthesize target molecules from 1,3-dicarbonyl compounds through many heterocyclization reactions. Method: The reaction of either 4-methylaniline (1a) or 1-naphthylamine (1b) with diethyl malonate (2) gave the anilide derivatives 3a and 3b, respectively. The latter products underwent a series of heterocyclization reactions to give the pyridine, pyran andthiazole derivatives which confirmed with the required spectral data. Results: Thein-vitro antitumor evaluations of the newly synthesized products against four cancer cell lines MCF-7, NCI-H460, SF-268 and WI 38 as normal cell line were screened and the data revealed that compounds 11a, 18b, 18c and 20d showed high antitumor activity and 20dindividualize with potential antitumor activity towards cell lines with lowest cytotoxicity effect. Both EGFR and PIM-1 enzyme inhibition were investigated for the compound 20d and his inhibition effect was promising for each enzyme showing IC50=45.67 ng and 553.3 ng for EGFR and PIM-1, respectively. Conclusion: Molecular docking results of compound 20d showed a strong binding interactions on both enzymes, where, good binding modes obtained on case of EGFR, which closely similar to the binding mode of standard Erlotinib. While, 20d showed complete superimposition binding interactions with VRV-cocrystallized ligand of PIM-1 that may expounds the in-vitro antitumor activity.

Investigations into the DNA-binding mode of doxorubicinone

2019 ◽  
Vol 17 (7) ◽  
pp. 1992-1998 ◽  
Author(s):  
Samuel Steucek Tartakoff ◽  
Jennifer M. Finan ◽  
Ellis J. Curtis ◽  
Haley M. Anchukaitis ◽  
Danielle J. Couture ◽  
...  
Keyword(s):  
Dna Binding ◽  
Binding Mode ◽  
Calorimetric Study ◽  
Binding Modes ◽  
Structural Homology

Spectroscopic and calorimetric study of DNA-binding by doxorubicin and doxorubicinone found different binding modes for the two molecules, despite their structural homology.

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