Understanding the molecular differential recognition of muramyl peptide ligands by LRR domains of human NOD receptors

2017 ◽  
Vol 474 (16) ◽  
pp. 2691-2711 ◽  
Author(s):  
Sukhithasri Vijayrajratnam ◽  
Anju Choorakottayil Pushkaran ◽  
Aathira Balakrishnan ◽  
Anil Kumar Vasudevan ◽  
Raja Biswas ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Hot Spot ◽  
Three Dimensional ◽  
Docking Studies ◽  
Peptide Ligands ◽  
Recognition Site ◽  
Diaminopimelic Acid ◽  
Ligand Recognition ◽  
Muramyl Peptide ◽  
Differential Recognition

Human nucleotide-binding oligomerization domain proteins, hNOD1 and hNOD2, are host intracellular receptors with C-terminal leucine-rich repeat (LRR) domains, which recognize specific bacterial peptidoglycan (PG) fragments as their ligands. The specificity of this recognition is dependent on the third amino acid of the stem peptide of the PG ligand, which is usually meso-diaminopimelic acid (mesoDAP) or l-lysine (l-Lys). Since the LRR domains of hNOD receptors had been experimentally shown to confer the PG ligand-sensing specificity, we developed three-dimensional structures of hNOD1-LRR and the hNOD2-LRR to understand the mechanism of differential recognition of muramyl peptide ligands by hNOD receptors. The hNOD1-LRR and hNOD2-LRR receptor models exhibited right-handed curved solenoid shape. The hot-spot residues experimentally proved to be critical for ligand recognition were located in the concavity of the NOD-LRR and formed the recognition site. Our molecular docking analyses and molecular electrostatic potential mapping studies explain the activation of hNOD-LRRs, in response to effective molecular interactions of PG ligands at the recognition site; and conversely, the inability of certain PG ligands to activate hNOD-LRRs, by deviations from the recognition site. Based on molecular docking studies using PG ligands, we propose few residues — G825, D826 and N850 in hNOD1-LRR and L904, G905, W931, L932 and S933 in hNOD2-LRR, evolutionarily conserved across different host species, which may play a major role in ligand recognition. Thus, our integrated experimental and computational approach elucidates the molecular basis underlying the differential recognition of PG ligands by hNOD receptors.

Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods

2021 ◽  
Vol 18 ◽  
Author(s):  
Jelena Bošković ◽  
Dušan Ružić ◽  
Olivera Čudina ◽  
Katarina Nikolic ◽  
Vladimir Dobričić
Keyword(s):  
Molecular Docking ◽  
External Validation ◽  
Three Dimensional ◽  
3D Qsar ◽  
Quantitative Structure Activity Relationship ◽  
Docking Studies ◽  
Qsar Analysis ◽  
In Silico Admet ◽  
Cox 2 ◽  
Lox Inhibitors

Background: Inflammation is common pathogenesis of many diseases progression, such as malignancy, cardiovascular and rheumatic diseases. The inhibition of the synthesis of inflammatory mediators by modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways provides a challenging strategy for the development of more effective drugs. Objective: The aim of this study was to design dual COX-2 and 5-LOX inhibitors with iron-chelating properties using a combination of ligand-based (three-dimensional quantitative structure-activity relationship (3D-QSAR)) and structure-based (molecular docking) methods. Methods: The 3D-QSAR analysis was applied on a literature dataset consisting of 28 dual COX-2 and 5-LOX inhibitors in Pentacle software. The quality of developed COX-2 and 5-LOX 3D-QSAR models were evaluated by internal and external validation methods. The molecular docking analysis was performed in GOLD software, while selected ADMET properties were predicted in ADMET predictor software. Results: According to the molecular docking studies, the class of sulfohydroxamic acid analogues, previously designed by 3D-QSAR, was clustered as potential dual COX-2 and 5-LOX inhibitors with iron-chelating properties. Based on the 3D-QSAR and molecular docking, 1j, 1g, and 1l were selected as the most promising dual COX-2 and 5-LOX inhibitors. According to the in silico ADMET predictions, all compounds had an ADMET_Risk score less than 7 and a CYP_Risk score lower than 2.5. Designed compounds were not estimated as hERG inhibitors, and 1j had improved intrinsic solubility (8.704) in comparison to the dataset compounds (0.411-7.946). Conclusion: By combining 3D-QSAR and molecular docking, three compounds (1j, 1g, and 1l) are selected as the most promising designed dual COX-2 and 5-LOX inhibitors, for which good activity, as well as favourable ADMET properties and toxicity, are expected.

scholarly journals SOLATION, CHARACTERIZATION, AND DOCKING STUDIES OF ISOLATED COMPOUNDS AS ANTIDIABETIC MOLECULES FROM CRESSA CRETICA

2020 ◽  
pp. 84-91
Author(s):  
SANGEETA RANI ◽  
KAVITA GAHLOT ◽  
ARVIND KUMAR
Keyword(s):  
Molecular Docking ◽  
Spectroscopic Analysis ◽  
Three Dimensional ◽  
Data Bank ◽  
Docking Study ◽  
Docking Studies ◽  
Dimensional Structure ◽  
Lead Target ◽  
Coarse Powder ◽  
Autodock 4.0

Objective: The purpose of this study was to investigate the diabetic effect of phytocompounds isolated from Cressa cretica Linn. using spectroscopic analysis and molecular docking studies. Methods: Coarse powder of the whole plant of C. cretica was extracted with methanol, extracted part was subjected to silica column isolation, and two compounds: 2-Isopropyl-4-(1-methyl-dodeca-2,4-dienyloxy)-benzene-1,3,5-triol (Compound CN-01) and 11-Methyl-dodeca-2,4,6,8,10-pentenoic acid 2,3-dihydroxy-5-methyl-phenyl ester (Compound CN-02) were isolated in pure form. The three-dimensional structure of target protein was downloaded from PDB (www.rcsb.org) Protein Data Bank, Ligand file CN – 01 and CN – 02 were converted to MDL Molfile (V2000) format using ChemSketch 2017.2.1. These files could not be used directly in AutoDock 4.0 tools; thus, they were first converted to PDB files using an open babel tool. Results: Compounds were revealed through spectroscopic analysis and screened using AutoDock 4.0 tools. Docking study recommended that CN – 01 and CN – 02 an existing phytochemical from the plant of C. cretica had the highest fitness docking score and hence could be a potent antidiabetic drug. Conclusion: In this investigation, we docked the receptor (glycogen phosphorylase protein) holds a promising lead target formation against diabetes based on molecular docking analysis (minimum hydrogen bond length and maximum docked score). Thus, these compounds can be effectively used as drugs for treating diabetes which is predicted on the basis of docking scores.

In Silico Studies against Viral Sexually Transmitted Diseases

2019 ◽  
Vol 20 (12) ◽  
pp. 1135-1150 ◽  
Author(s):  
Alex F.M. Monteiro ◽  
Jessika de Oliveira Viana ◽  
Engene Muratov ◽  
Marcus T. Scotti ◽  
Luciana Scotti
Keyword(s):  
Molecular Docking ◽  
Sexually Transmitted Diseases ◽  
Ebola Virus ◽  
Structural Characteristics ◽  
Three Dimensional ◽  
Docking Studies ◽  
Sexually Transmitted ◽  
Drug Candidates ◽  
Clinical Syndromes ◽  
In Silico Studies

Sexually Transmitted Diseases (STDs) refer to a variety of clinical syndromes and infections caused by pathogens that can be acquired and transmitted through sexual activity. Among STDs widely reported in the literature, viral sexual diseases have been increasing in a number of cases globally. This emphasizes the need for prevention and treatment. Among the methods widely used in drug planning are Computer-Aided Drug Design (CADD) studies and molecular docking which have the objective of investigating molecular interactions between two molecules to better understand the three -dimensional structural characteristics of the compounds. This review will discuss molecular docking studies applied to viral STDs, such as Ebola virus, Herpes virus and HIV, and reveal promising new drug candidates with high levels of specificity to their respective targets.

Bacterial peptidoglycan with amidated meso-diaminopimelic acid evades NOD1 recognition: an insight into NOD1 structure–recognition

2016 ◽  
Vol 473 (24) ◽  
pp. 4573-4592 ◽  
Author(s):  
Sukhithasri Vijayrajratnam ◽  
Anju Choorakottayil Pushkaran ◽  
Aathira Balakrishnan ◽  
Anil Kumar Vasudevan ◽  
Raja Biswas ◽  
...  
Keyword(s):  
Hot Spot ◽  
Recognition Site ◽  
Diaminopimelic Acid ◽  
Computational Techniques ◽  
Biomolecular Recognition ◽  
Recognition Mechanism ◽  
Structure Recognition ◽  
Evolutionarily Conserved ◽  
Bacterial Peptidoglycan ◽  
Relationship Of

Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an intracellular pattern recognition receptor that recognizes bacterial peptidoglycan (PG) containing meso-diaminopimelic acid (mesoDAP) and activates the innate immune system. Interestingly, a few pathogenic and commensal bacteria modify their PG stem peptide by amidation of mesoDAP (mesoDAPNH2). In the present study, NOD1 stimulation assays were performed using bacterial PG containing mesoDAP (PGDAP) and mesoDAPNH2 (PGDAPNH2) to understand the differences in their biomolecular recognition mechanism. PGDAP was effectively recognized, whereas PGDAPNH2 showed reduced recognition by the NOD1 receptor. Restimulation of the NOD1 receptor, which was initially stimulated with PGDAP using PGDAPNH2, did not show any further NOD1 activation levels than with PGDAP alone. But the NOD1 receptor initially stimulated with PGDAPNH2 responded effectively to restimulation with PGDAP. The biomolecular structure–recognition relationship of the ligand-sensing leucine-rich repeat (LRR) domain of human NOD1 (NOD1–LRR) with PGDAP and PGDAPNH2 was studied by different computational techniques to further understand the molecular basis of our experimental observations. The d-Glu–mesoDAP motif of GMTPDAP, which is the minimum essential motif for NOD1 activation, was found involved in specific interactions at the recognition site, but the interactions of the corresponding d-Glu–mesoDAP motif of PGDAPNH2 occur away from the recognition site of the NOD1 receptor. Hot-spot residues identified for effective PG recognition by NOD1–LRR include W820, G821, D826 and N850, which are evolutionarily conserved across different host species. These integrated results thus successfully provided the atomic level and biochemical insights on how PGs containing mesoDAPNH2 evade NOD1–LRR receptor recognition.

scholarly journals Ligand docking and binding site analysis with pymol and autodock/vina

2015 ◽  
Vol 4 (2) ◽  
pp. 168 ◽  
Author(s):  
Mohd. Ahmar Rauf ◽  
Swaleha Zubair ◽  
Asim Azhar
Keyword(s):  
Molecular Docking ◽  
Drug Design ◽  
Three Dimensional ◽  
Structural Features ◽  
Docking Studies ◽  
Ligand Docking ◽  
Structure Based Drug Design ◽  
Site Analysis ◽  
User Friendly ◽  
Autodock 4.2

<p>Docking of various therapeutically important chemical entities to the specific target sites offers a meaningful strategy that may have tremendous scope in a drug design process. For a thorough understanding of the structural features that determine the strength of bonding between a ligand with its receptor, an insight to visualize binding geometries and interaction is mandatory. Bioinformatical as well as graphical software ‘PyMOL’ in combination with the molecular docking suites Autodock and Vina allows the study of molecular combination to visualize and understand the structure-based drug design efforts. In the present study, we outlined a user friendly method to perform molecular docking using vina and finally the results were analyzed in pymol in both two as well as three-dimensional orientation. The operation bypasses the steps that are involved in docking using cygwin terminal like formation of gpf and dpf files. The simple and straight-forward operation method does not require formal bioinformatics training to apprehend molecular docking studies using AutoDock 4.2 program.</p>

scholarly journals Docking studies in targeting proteins involved in cardiovascular disorders using phytocompounds from Terminalia arjuna

2020 ◽  
Author(s):  
Vikas Kumar ◽  
Nitin Sharma ◽  
Anuradha Sourirajan ◽  
Prem Kumar Khosla ◽  
Kamal Dev
Keyword(s):  
Molecular Docking ◽  
3D Structure ◽  
Three Dimensional ◽  
Data Bank ◽  
Docking Studies ◽  
Terminalia Arjuna ◽  
Structure Based Drug Design ◽  
Lipinski’S Rule ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

AbstractTerminalia arjuna (Roxb.) Wight and Arnot (T. arjuna) commonly known as Arjuna has been known for its cardiotonic nature in heart failure, ischemic, cardiomyopathy, atherosclerosis, myocardium necrosis and also has been used in the treatment of different human disorders such as blood diseases, anaemia and viral diseases. Our focus has been on phytochemicals which do not exhibit any cytotoxicity and have significant cardioprotective activity. Since Protein-Ligand interactions play a key role in structure-based drug design, therefore with the help of molecular docking, we screened 19 phytochemicals present in T. arjuna and investigated their binding affinity against different cardiovascular target proteins. The three-dimensional (3D) structure of target cardiovascular proteins were retrieved from Protein Data Bank, and docked with 3D Pubchem structures of 19 phytochemicals using Autodock vina. Molecular docking and drug-likeness studies were made using ADMET properties while Lipinski’s rule of five was performed for the phytochemicals to evaluate their cardio protective activity. Among all selected phytocompounds, arjunic acid, arjungenin, and terminic acid were found to fulfill all ADMET rules, drug likeness, and are less toxic in nature. Our studies, therefore revealed that these three phytochemicals from T. arjuna can be used as promising candidates for developing broad spectrum drugs against cardiovascular diseases.

scholarly journals Potential Inhibitors of Galactofuranosyltransferase 2 (GlfT2): Molecular Docking, 3D-QSAR, and In Silico ADMETox Studies

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Christopher Llynard D. Ortiz ◽  
Gladys C. Completo ◽  
Ruel C. Nacario ◽  
Ricky B. Nellas
Keyword(s):  
Cell Wall ◽  
Molecular Docking ◽  
Binding Energy ◽  
In Silico ◽  
Effective Interaction ◽  
Three Dimensional ◽  
3D Qsar ◽  
Quantitative Structure Activity Relationship ◽  
Docking Studies ◽  
Design And Synthesis

AbstractA strategy in the discovery of anti-tuberculosis (anti-TB) drug involves targeting the enzymes involved in the biosynthesis of Mycobacterium tuberculosis’ (Mtb) cell wall. One of these enzymes is Galactofuranosyltransferase 2 (GlfT2) that catalyzes the elongation of the galactan chain of Mtb cell wall. Studies targeting GlfT2 have so far produced compounds showing minimal inhibitory activity. With the current challenge of designing potential GlfT2 inhibitors with high inhibition activity, computational methods such as molecular docking, receptor-ligand mapping, molecular dynamics, and Three-Dimensional-Quantitative Structure-Activity Relationship (3D-QSAR) were utilized to deduce the interactions of the reported compounds with the target enzyme and enabling the design of more potent GlfT2 inhibitors. Molecular docking studies showed that the synthesized compounds have binding energy values between −3.00 to −6.00 kcal mol−1. Two compounds, #27 and #31, have registered binding energy values of −8.32 ± 0.01, and −8.08 ± 0.01 kcal mol−1, respectively. These compounds were synthesized as UDP-Galactopyranose mutase (UGM) inhibitors and could possibly inhibit GlfT2. Interestingly, the analogs of the known disaccharide substrate, compounds #1–4, have binding energy range of −10.00 to −19.00 kcal mol−1. The synthesized and newly designed compounds were subjected to 3D-QSAR to further design compounds with effective interaction within the active site. Results showed improved binding energy from −6.00 to −8.00 kcal mol−1. A significant increase on the binding affinity was observed when modifying the aglycon part instead of the sugar moiety. Furthermore, these top hit compounds were subjected to in silico ADMETox evaluation. Compounds #31, #70, #71, #72, and #73 were found to pass the ADME evaluation and throughout the screening, only compound #31 passed the predicted toxicity evaluation. This work could pave the way in the design and synthesis of GlfT2 inhibitors through computer-aided drug design and can be used as an initial approach in identifying potential novel GlfT2 inhibitors with promising activity and low toxicity.

scholarly journals MOLECULAR DOCKING STUDIES OF ISOLATED FLAVONOIDS COMPOUNDS FROM AMARANTHUS TRISTIS LINN. AS ALPHA-AMYLASE AND ALPHA-GLUCOSIDASE ACTIVATORS

2018 ◽  
Vol 11 ◽  
Author(s):  
Sundar Rajan T ◽  
Vijey Aanandhi M
Keyword(s):  
Molecular Docking ◽  
Experimental Studies ◽  
Three Dimensional ◽  
Data Bank ◽  
Docking Studies ◽  
Alpha Amylase ◽  
Dimensional Structure ◽  
Novel Targets ◽  
Alpha Glucosidase ◽  
Protein Data Bank Database

Aim: Aim of this work on in silico approach to used to access the use of flavonids compounds of nutritionally enriched plant Amaranthus tristis Linn.Methods: Bioflavonoids of rutin isolated from A. tristis Linn. and active agents receptor such as alpha-amylase (1SMD) and alpha-glucosidase (3wy1) activators. Three-dimensional structure of receptors was obtained from protein data bank database and biocomponents such as isoflavones and flavonones of A. tristis were downloaded from database like USDA. Docking studies of insulin receptor with A. tristis biocomponents for isoflavones and flavonones were performed using AutoDock - 1.5.6 software.Results: Compounds from A. tristis Linn. showed better binding features with the alpha-amylase and alpha-glycosidase. Thus, these compounds can be effectively used as drugs for treating diabetes which is predicted on the basis of docking scores.Conclusion: The insights gained in this work can be further used in experimental studies for designing antidiabetic drugs with novel targets and mode of action.

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