Computational Analysis of Dipyrone Metabolite 4-Aminoantipyrine As A Cannabinoid Receptor 1 Agonist

2020 ◽  
Vol 27 (28) ◽  
pp. 4741-4749 ◽  
Author(s):  
Silvana Russo ◽  
Walter Filgueira de Azevedo
Keyword(s):  
Cannabinoid Receptor ◽  
Computational Study ◽  
Structural Basis ◽  
Crystallographic Structure ◽  
Cannabinoid Receptor 1 ◽  
Docking Simulations ◽  
Functional Studies ◽  
Protein Ligand Interactions ◽  
Mechanistic Analysis ◽  
Ligand Interactions

Background: Cannabinoid receptor 1 has its crystallographic structure available in complex with agonists and inverse agonists, which paved the way to establish an understanding of the structural basis of interactions with ligands. Dipyrone is a prodrug with analgesic capabilities and is widely used in some countries. Recently some evidence of a dipyrone metabolite acting over the Cannabinoid Receptor 1has been shown. Objective: Our goal here is to explore the dipyrone metabolite 4-aminoantipyrine as a Cannabinoid Receptor 1 agonist, reviewing dipyrone characteristics, and investigating the structural basis for its interaction with the Cannabinoid Receptor 1. Method: We reviewed here recent functional studies related to the dipyrone metabolite focusing on its action as a Cannabinoid Receptor 1 agonist. We also analyzed protein-ligand interactions for this complex obtained through docking simulations against the crystallographic structure of the Cannabinoid Receptor 1. Results: Analysis of the crystallographic structure and docking simulations revealed that most of the interactions present in the docked pose were also present in the crystallographic structure of Cannabinoid Receptor 1 and agonist. Conclusion: Analysis of the complex of 4-aminoantipyrine and Cannabinoid Receptor 1 revealed the pivotal role played by residues Phe 170, Phe 174, Phe 177, Phe 189, Leu 193, Val 196, and Phe 379, besides the conserved hydrogen bond at Ser 383. The mechanistic analysis and the present computational study suggest that the dipyrone metabolite 4-aminoantipyrine interacts with the Cannabinoid Receptor 1.

Improving protein–ligand binding prediction by considering the bridging water molecules in Autodock

2019 ◽  
Vol 18 (05) ◽  
pp. 1950027 ◽  
Author(s):  
Qiangna Lu ◽  
Lian-Wen Qi ◽  
Jinfeng Liu
Keyword(s):  
Ligand Binding ◽  
Considerable Improvement ◽  
Ligand Docking ◽  
Water Molecules ◽  
Binding Modes ◽  
Binding Prediction ◽  
Docking Simulations ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Docking Program

Water plays a significant role in determining the protein–ligand binding modes, especially when water molecules are involved in mediating protein–ligand interactions, and these important water molecules are receiving more and more attention in recent years. Considering the effects of water molecules has gradually become a routine process for accurate description of the protein–ligand interactions. As a free docking program, Autodock has been most widely used in predicting the protein–ligand binding modes. However, whether the inclusion of water molecules in Autodock would improve its docking performance has not been systematically investigated. Here, we incorporate important bridging water molecules into Autodock program, and systematically investigate the effectiveness of these water molecules in protein–ligand docking. This approach was evaluated using 18 structurally diverse protein–ligand complexes, in which several water molecules bridge the protein–ligand interactions. Different treatment of water molecules were tested by using the fixed and rotatable water molecules, and a considerable improvement in successful docking simulations was found when including these water molecules. This study illustrates the necessity of inclusion of water molecules in Autodock docking, and emphasizes the importance of a proper treatment of water molecules in protein–ligand binding predictions.

Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues

2014 ◽  
Vol 395 (7-8) ◽  
pp. 891-903 ◽  
Author(s):  
Anastasia Tziridis ◽  
Daniel Rauh ◽  
Piotr Neumann ◽  
Petr Kolenko ◽  
Anja Menzel ◽  
...  
Keyword(s):  
Binding Site ◽  
Proteinase Inhibitors ◽  
Factor Xa ◽  
Serine Proteinase ◽  
Crystallographic Structure ◽  
Binding Modes ◽  
Ligand Complex ◽  
Structure Based Drug Design ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

Abstract A high-resolution crystallographic structure determination of a protein–ligand complex is generally accepted as the ‘gold standard’ for structure-based drug design, yet the relationship between structure and affinity is neither obvious nor straightforward. Here we analyze the interactions of a series of serine proteinase inhibitors with trypsin variants onto which the ligand-binding site of factor Xa has been grafted. Despite conservative mutations of only two residues not immediately in contact with ligands (second shell residues), significant differences in the affinity profiles of the variants are observed. Structural analyses demonstrate that these are due to multiple effects, including differences in the structure of the binding site, differences in target flexibility and differences in inhibitor binding modes. The data presented here highlight the myriad competing microscopic processes that contribute to protein–ligand interactions and emphasize the difficulties in predicting affinity from structure.

scholarly journals Chemical shift imprint of intersubunit communication in a symmetric homodimer

2016 ◽  
Vol 113 (34) ◽  
pp. 9533-9538 ◽  
Author(s):  
Bradley T. Falk ◽  
Paul J. Sapienza ◽  
Andrew L. Lee
Keyword(s):  
Protein Function ◽  
Isotopic Labeling ◽  
Structural Basis ◽  
Oligomeric Proteins ◽  
Protein Ligand Interactions ◽  
Allosteric Communication ◽  
Binding Event ◽  
Ligand Interactions ◽  
Intersubunit Communication ◽  
Specific Ligand

Allosteric communication is critical for protein function and cellular homeostasis, and it can be exploited as a strategy for drug design. However, unlike many protein–ligand interactions, the structural basis for the long-range communication that underlies allostery is not well understood. This lack of understanding is most evident in the case of classical allostery, in which a binding event in one protomer is sensed by a second symmetric protomer. A primary reason why study of interdomain signaling is challenging in oligomeric proteins is the difficulty in characterizing intermediate, singly bound species. Here, we use an NMR approach to isolate and characterize a singly ligated state (“lig1”) of a homodimeric enzyme that is otherwise obscured by rapid exchange with apo and saturated forms. Mixed labeled dimers were prepared that simultaneously permit full population of the lig1 state and isotopic labeling of either protomer. Direct visualization of peaks from lig1 yielded site-specific ligand-state multiplets that provide a convenient format for assessing mechanisms of intersubunit communication from a variety of NMR measurements. We demonstrate this approach on thymidylate synthase from Escherichia coli, a homodimeric enzyme known to be half-the-sites reactive. Resolving the dUMP1 state shows that active site communication occurs not upon the first dUMP binding, but upon the second. Surprisingly, for many sites, dUMP1 peaks are found beyond the limits set by apo and dUMP2 peaks, indicating that binding the first dUMP pushes the enzyme ensemble to further conformational extremes than the apo or saturated forms. The approach used here should be generally applicable to homodimers.

scholarly journals Identification and design of vinyl sulfone inhibitors against Cryptopain-1 – a cysteine protease from cryptosporidiosis-causing Cryptosporidium parvum

2018 ◽  
Author(s):  
Arpita Banerjee
Keyword(s):  
Cryptosporidium Parvum ◽  
Cysteine Protease ◽  
Drug Targets ◽  
Computational Study ◽  
Cathepsin L ◽  
Cysteine Proteases ◽  
Vinyl Sulfone ◽  
Docking Simulations ◽  
Stunted Growth ◽  
Ligand Interactions

AbstractCryptosporidiosis, a disease marked by diarrhea in adults and stunted growth in children, is associated with the unicellular protozoan pathogen Cryptosporidium; often the species parvum. Cryptopain-1, a cysteine protease characterized in the genome of Cryptosporidium parvum, had been earlier shown to be inhibited by a vinyl sulfone compound called K11777 (or K-777). Cysteine proteases have long been established as valid drug targets, which can be covalently and selectively inhibited by vinyl sulfones. This computational study was initiated to identify purchasable vinyl sulfone compounds, which could possibly inhibit cryptopain-1 with higher efficacy than K11777. Docking simulations screened a number of such possibly better inhibitors. The work was furthered to probe the enzymatic pocket of cryptopain-1, through in-silico mutations, to derive a map of receptor-ligand interactions in the docked complexes. The idea was to provide crucial clues to aid the design of inhibitors, which would be able to bind the protease well by making favorable interactions with important residues of the enzyme. The analyses dictated placement of ligands towards the front of the enzymatic cleft, and disfavored interactions deep within. The S1’ and S2 subsites of the enzyme preferred to remain occupied by polar ligand subgroups. Reasonably distanced ring systems and polar backbones of ligands were desired across the cleft. Large as well as inflexible subgroups were not tolerated. Double ringed systems such as substituted napthalene, especially in S1, were exceptions though. The S2 subsite, which is typically a specificity determinant in papain (C1) family cysteine proteases such as cathepsin L-like cryptopain-1, can possibly accommodate polar and hydrophobic ligand subgroups alike.

Identification of Novel Potential Anti-Diabetic Candidates targeting Human Pancreatic ɑ-Amylase and Human ɑ-Glycosidase: An Exhaustive Structure-based Screening

2021 ◽  
Author(s):  
Deepika Maliwal ◽  
Raghuvir R. S. Pissurlenkar ◽  
Vikas Telvekar
Keyword(s):  
Medical Condition ◽  
Computational Study ◽  
Well Being ◽  
Vital Role ◽  
The Body ◽  
Free Energies ◽  
Protein Ligand Interactions ◽  
Depth Analysis ◽  
Ligand Interactions ◽  
Binding Free Energies

Diabetes is a major health issue that half a billion people affected worldwide. It is a serious, long-term medical condition majorly impacting the lives and well-being of individuals, families, and societies at large. It is amongst the top 10 diseases responsible for the death amongst adults with an expected rise to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045. The carbohydrates absorbed into the body are hydrolyzed by pancreatic α-amylase and other enzymes, human α-glucosidase. The α-amylase and α-glucosidase are validated therapeutic targets in the treatment of Type II diabetes (T2DM) as they play a vital role in modulating the blood glucose post meal. Herein, we report novel and diverse molecules as potential candidates, with predicted affinity for α-amylase and α-glucosidase. These molecules have been identified via hierarchical multistep docking of small molecules database with the estimated binding free energies. A Glide XP Score cutoff −8.00 kcal/mol was implemented to filter out non potential molecules. Four molecules viz. amb22034702, amb18105639, amb17153304, and amb9760832 have been identified after an exhaustive computational study involving, evaluation of binding interactions and assessment of the pharmacokinetics and toxicity profiles. The in-depth analysis of protein– ligand interactions was performed using a 100ns molecular dynamics (MD) simulation to establish the dynamic stability. Furthermore MM-GBSA based binding free energies were computed for 1000 trajectory snapshots to ascertain the strong binding affinity of these molecules for α-amylase and αglucosidase. The identified molecules can be considered as promising candidates for further drug development through necessary experimental assessments.

Advances in the Understanding of the Cannabinoid Receptor 1 – Focusing on the Inverse Agonists Interactions

2019 ◽  
Vol 26 (10) ◽  
pp. 1908-1919 ◽  
Author(s):  
Silvana Russo ◽  
Walter Filgueira De Azevedo
Keyword(s):  
Hydrogen Bonds ◽  
Intermolecular Interactions ◽  
Cannabinoid Receptor ◽  
Structural Information ◽  
New Drugs ◽  
Crystallographic Structure ◽  
Complex Structures ◽  
Cannabinoid Receptor 1 ◽  
Intermolecular Hydrogen Bonds ◽  
Inverse Agonists

Background: Cannabinoid Receptor 1 (CB1) is a membrane protein prevalent in the central nervous system, whose crystallographic structure has recently been solved. Studies will be needed to investigate CB1 complexes with its ligands and its role in the development of new drugs. Objective: Our goal here is to review the studies on CB1, starting with general aspects and focusing on the recent structural studies, with emphasis on the inverse agonists bound structures. Methods: We start with a literature review, and then we describe recent studies on CB 1 crystallographic structure and docking simulations. We use this structural information to depict protein-ligand interactions. We also describe the molecular docking method to obtain complex structures of CB 1 with inverse agonists. Results: Analysis of the crystallographic structure and docking results revealed the residues responsible for the specificity of the inverse agonists for CB 1. Most of the intermolecular interactions involve hydrophobic residues, with the participation of the residues Phe 170 and Leu 359 in all complex structures investigated in the present study. For the complexes with otenabant and taranabant, we observed intermolecular hydrogen bonds involving residues His 178 (otenabant) and Thr 197 and Ser 383 (taranabant). Conclusion: Analysis of the structures involving inverse agonists and CB 1 revealed the pivotal role played by residues Phe 170 and Leu 359 in their interactions and the strong intermolecular hydrogen bonds highlighting the importance of the exploration of intermolecular interactions in the development of novel inverse agonists.

Sign in / Sign up

Export Citation Format

Share Document