scholarly journals Molecular Docking and Dynamic Simulation of UDP-N-Acetylenolpyruvoylglucosamine Reductase (MurB) Obtained from Mycobacterium Tuberculosis Using in Silico Approach

2020 ◽  
Author(s):  
Mustafa Alhaji Isa ◽  
Mohammed Mustapha Mohammed
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Binding Site ◽  
Md Simulation ◽  
Simulation Analysis ◽  
Data Bank ◽  
Binding Energies ◽  
Peptidoglycan Biosynthesis

<p>The UDP-N-acetylenolpyruvoylglucosamine reductase (MurB) catalyze the final steps of the UDP-N-acetylmuramic acid (UDPMurNAc) formation in the peptidoglycan biosynthesis pathway. The absence of this pathway in mammal made it an attractive target for drug development in <i>Mycobacterium tuberculosis</i> (MTB). In this study, the crystal structure of MurB from MTB (PDB Code: 5JZX and resolution of 2.2 Å) bound to FAD and K<sup>+</sup> was obtained from Protein Data Bank (PDB). A total of 2157 compounds with best binding conformations obtained from zinc database through virtual screening. These compounds further screened for drug-likeness, pharmacokinetic properties, physicochemical properties (Lipinski rule of five), and molecular docking analysis to obtained compounds with desirable therapeutic properties and good binding energies against MurB. Seven compounds (7) with minimum binding energies ranged between ─11.80 and ─10.39kcal/mol were selected, lower than the binding energy of FAD (─10.06kcal/mol). Four compounds with best binding energies (ZINC19837204 = ─11.80kcal/mol, ZINC11839554 = ─11.47kcal/mol, ZINC14976552 = ─10.77kcal/mol) and ability to interact with the residues (ZINC12242812 = ─10.39kcal/mol) of the substrate binding site further selected for the molecular dynamic (MD) simulation analysis. The result of the MD simulation showed that all the four ligands formed stable complexes in the binding site of the MurB, during the 50ns MD simulation, when compared with the cofactor (FAD). Therefore, these compounds were proposed to be novel inhibitors of MTB after <i>in vivo</i> and <i>in vitro</i> validation.</p>

Molecular Docking and Dynamic Simulation of UDP-N-Acetylenolpyruvoylglucosamine Reductase (MurB) Obtained from Mycobacterium Tuberculosis Using in Silico Approach

2020 ◽  
Author(s):  
Mustafa Alhaji Isa ◽  
Mohammed Mustapha Mohammed
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Binding Site ◽  
Md Simulation ◽  
Simulation Analysis ◽  
Data Bank ◽  
Binding Energies ◽  
Peptidoglycan Biosynthesis

<p>The UDP-N-acetylenolpyruvoylglucosamine reductase (MurB) catalyze the final steps of the UDP-N-acetylmuramic acid (UDPMurNAc) formation in the peptidoglycan biosynthesis pathway. The absence of this pathway in mammal made it an attractive target for drug development in <i>Mycobacterium tuberculosis</i> (MTB). In this study, the crystal structure of MurB from MTB (PDB Code: 5JZX and resolution of 2.2 Å) bound to FAD and K<sup>+</sup> was obtained from Protein Data Bank (PDB). A total of 2157 compounds with best binding conformations obtained from zinc database through virtual screening. These compounds further screened for drug-likeness, pharmacokinetic properties, physicochemical properties (Lipinski rule of five), and molecular docking analysis to obtained compounds with desirable therapeutic properties and good binding energies against MurB. Seven compounds (7) with minimum binding energies ranged between ─11.80 and ─10.39kcal/mol were selected, lower than the binding energy of FAD (─10.06kcal/mol). Four compounds with best binding energies (ZINC19837204 = ─11.80kcal/mol, ZINC11839554 = ─11.47kcal/mol, ZINC14976552 = ─10.77kcal/mol) and ability to interact with the residues (ZINC12242812 = ─10.39kcal/mol) of the substrate binding site further selected for the molecular dynamic (MD) simulation analysis. The result of the MD simulation showed that all the four ligands formed stable complexes in the binding site of the MurB, during the 50ns MD simulation, when compared with the cofactor (FAD). Therefore, these compounds were proposed to be novel inhibitors of MTB after <i>in vivo</i> and <i>in vitro</i> validation.</p>

scholarly journals Virtual Screening, Molecular Docking and Dynamic Simulation of Shikimate Kinase from Mycobacterium Tuberculosis Using in Silico Approach

2020 ◽  
Author(s):  
Dr. Mustafa Alhaji Isa
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Binding Site ◽  
Md Simulation ◽  
Simulation Analysis ◽  
3D Structure ◽  
Normal Function ◽  
Binding Energies ◽  
Shikimate Kinase ◽  
Lipinski’S Rule

<p>Shikimate kinase (SK) is an enzyme that catalyzes the fifth steps in the shikimate pathway. The enzyme facilitate the transfer of phosphoryl from ATP to shikimate, to produce ADP and shikimate-3-phosphate from <i>Mycobacterium tuberculosis</i> (MTB). The 3D structure of SK bound ligands (4-(2-Hydroxyethyl)-1-Piperazine Ethanesulfonic Acid (EPE)), ADP and metals (Mg2+, Cl- and Pt+) obtained from PDB (PDB ID: 1L4U and resolution 1.8Å). The structural analysis of the SK revealed that it has a substrate or shikimate binding site (Asp34, Arg58, and Lys136) and substrate binding via amide nitrogen (Gly80). It also possessed nucleotide binding region (Gly12─Thr17), the ATP binding site (Arg117 and Arg153) and metallic ion (Mg2+) binding site (Ser16 and Asp32). All these residues mentioned above play an essential role in the catalytic activity of the SK. Therefore inhibition any of these residues serve as a stumbling block for the normal function of the enzyme. A total of eleven thousand three hundred and twenty-three (11323) compounds obtained from two public databases (Zinc Database and PubChem) capable of binding to SK with good binding affinities. These compounds further filtered for Lipinski’s rule of five, drug-likeness, molecular docking analysis, and ADME and toxicity analysis. Three compounds with minimum binding energies─ PubChem15478 (─11.75 kcal/mol), ZINC02838601 (─11.52 kcal/mol), and ZINC11790367 (─9.88 kcal/mol) ─were selected and used for the MD simulation analysis. Also, MD simulation of the SK bound to EPE, ADP, and Mg2+ were carried out to compare their stabilities with the selected protein-ligand complexes. The result showed that the two compounds (ZINC11790367 and PubChem15478) formed stable and rigid complexes comparable to the bound ligand and the cofactors during the 50ns MD simulation. Therefore, it concluded that the above mentioned two compounds capable of inhibiting SK considered as prospective drugs for MTB after successful experimental validation.</p>

scholarly journals Virtual Screening, Molecular Docking and Dynamic Simulation of Shikimate Kinase from Mycobacterium Tuberculosis Using in Silico Approach

2020 ◽  
Author(s):  
Dr. Mustafa Alhaji Isa
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Binding Site ◽  
Md Simulation ◽  
Simulation Analysis ◽  
3D Structure ◽  
Normal Function ◽  
Binding Energies ◽  
Shikimate Kinase ◽  
Lipinski’S Rule

<p>Shikimate kinase (SK) is an enzyme that catalyzes the fifth steps in the shikimate pathway. The enzyme facilitate the transfer of phosphoryl from ATP to shikimate, to produce ADP and shikimate-3-phosphate from <i>Mycobacterium tuberculosis</i> (MTB). The 3D structure of SK bound ligands (4-(2-Hydroxyethyl)-1-Piperazine Ethanesulfonic Acid (EPE)), ADP and metals (Mg2+, Cl- and Pt+) obtained from PDB (PDB ID: 1L4U and resolution 1.8Å). The structural analysis of the SK revealed that it has a substrate or shikimate binding site (Asp34, Arg58, and Lys136) and substrate binding via amide nitrogen (Gly80). It also possessed nucleotide binding region (Gly12─Thr17), the ATP binding site (Arg117 and Arg153) and metallic ion (Mg2+) binding site (Ser16 and Asp32). All these residues mentioned above play an essential role in the catalytic activity of the SK. Therefore inhibition any of these residues serve as a stumbling block for the normal function of the enzyme. A total of eleven thousand three hundred and twenty-three (11323) compounds obtained from two public databases (Zinc Database and PubChem) capable of binding to SK with good binding affinities. These compounds further filtered for Lipinski’s rule of five, drug-likeness, molecular docking analysis, and ADME and toxicity analysis. Three compounds with minimum binding energies─ PubChem15478 (─11.75 kcal/mol), ZINC02838601 (─11.52 kcal/mol), and ZINC11790367 (─9.88 kcal/mol) ─were selected and used for the MD simulation analysis. Also, MD simulation of the SK bound to EPE, ADP, and Mg2+ were carried out to compare their stabilities with the selected protein-ligand complexes. The result showed that the two compounds (ZINC11790367 and PubChem15478) formed stable and rigid complexes comparable to the bound ligand and the cofactors during the 50ns MD simulation. Therefore, it concluded that the above mentioned two compounds capable of inhibiting SK considered as prospective drugs for MTB after successful experimental validation.</p>

scholarly journals in Silico Docking and Molecular Dynamic Simulation of 3-Dehydroquinate Dehydratase from Mycobacterium Tuberculosis Through Virtual Screening and Pharmacokinetics Studies

2020 ◽  
Author(s):  
Mustafa Alhaji Isa ◽  
Muhammad M Ibrahim
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Virtual Screening ◽  
Molecular Dynamic ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
In Silico Docking ◽  
Pharmacokinetic Properties

The 3-hydroquinate synthase (DHQase) is an enzyme that catalyzes the third step of the shikimate pathway in <i>Mycobacterium tuberculosis</i> (MTB), by converting 3-dehydroquinate into 3-dehydroshikimate. In this study, the novel inhibitors of DHQase from MTB was identified using in silico approach. The crystal structure of DHQase bound to 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic acid (CA) obtained from the Protein Data Bank (PDB ID: 3N76). The structure prepared through energy minimization and structure optimization. A total of 9699 compounds obtained from Zinc and PubChem databases capable of binding to DHQase and subjected to virtual screening through Lipinski’s rule of five and molecular docking analysis. Eight (8) compounds with good binding energies, ranged between ─8.99 to ─8.39kcal/mol were selected, better than the binding energy of ─4.93kcal/mol for CA and further filtered for pharmacokinetic properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity or ADMET). Five compounds (ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077) which had desirable pharmacokinetic properties selected for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses showed that all the compounds formed stable and rigid complexes after the 50ns MD simulation and also had a lower binding as compared to CA. Therefore, these compounds considered as good inhibitors of MTB after in vitro and in vivo validation.”

scholarly journals in Silico Docking and Molecular Dynamic Simulation of 3-Dehydroquinate Dehydratase from Mycobacterium Tuberculosis Through Virtual Screening and Pharmacokinetics Studies

2020 ◽  
Author(s):  
Mustafa Alhaji Isa ◽  
Muhammad M Ibrahim
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Virtual Screening ◽  
Molecular Dynamic ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
In Silico Docking ◽  
Pharmacokinetic Properties

The 3-hydroquinate synthase (DHQase) is an enzyme that catalyzes the third step of the shikimate pathway in <i>Mycobacterium tuberculosis</i> (MTB), by converting 3-dehydroquinate into 3-dehydroshikimate. In this study, the novel inhibitors of DHQase from MTB was identified using in silico approach. The crystal structure of DHQase bound to 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic acid (CA) obtained from the Protein Data Bank (PDB ID: 3N76). The structure prepared through energy minimization and structure optimization. A total of 9699 compounds obtained from Zinc and PubChem databases capable of binding to DHQase and subjected to virtual screening through Lipinski’s rule of five and molecular docking analysis. Eight (8) compounds with good binding energies, ranged between ─8.99 to ─8.39kcal/mol were selected, better than the binding energy of ─4.93kcal/mol for CA and further filtered for pharmacokinetic properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity or ADMET). Five compounds (ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077) which had desirable pharmacokinetic properties selected for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses showed that all the compounds formed stable and rigid complexes after the 50ns MD simulation and also had a lower binding as compared to CA. Therefore, these compounds considered as good inhibitors of MTB after in vitro and in vivo validation.”

scholarly journals Phloroglucinol as a Potential Candidate against Trypanosoma congolense Infection: Insights from In Vivo, In Vitro, Molecular Docking and Molecular Dynamic Simulation Analyses

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 469
Author(s):  
Nasirudeen Idowu Abdulrashid ◽  
Suleiman Aminu ◽  
Rahma Muhammad Adamu ◽  
Nasir Tajuddeen ◽  
Murtala Bindawa Isah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Studies ◽  
Binding Energies ◽  
Sub Saharan Africa ◽  
Dynamics Simulation ◽  
Potential Candidate ◽  
Inhibitory Effects ◽  
Hydrogen Bond Interaction

Sub-Saharan Africa is profoundly challenged with African Animal Trypanosomiasis and the available trypanocides are faced with drawbacks, necessitating the search for novel agents. Herein, the chemotherapeutic potential of phloroglucinol on T. congolense infection and its inhibitory effects on the partially purified T. congolense sialidase and phospholipase A2 (PLA2) were investigated. Treatment with phloroglucinol for 14 days significantly (p < 0.05) suppressed T. congolense proliferation, increased animal survival and ameliorated anemia induced by the parasite. Using biochemical and histopathological analyses, phloroglucinol was found to prevent renal damages and splenomegaly, besides its protection against T. congolense-associated increase in free serum sialic acids in infected animals. Moreover, the compound inhibited bloodstream T. congolense sialidase via mixed inhibition pattern with inhibition binding constant (Ki) of 0.181 µM, but a very low uncompetitive inhibitory effects against PLA2 (Ki > 9000 µM) was recorded. Molecular docking studies revealed binding energies of −4.9 and −5.3 kcal/mol between phloroglucinol with modeled sialidase and PLA2 respectively, while a 50 ns molecular dynamics simulation using GROMACS revealed the sialidase-phloroglucinol complex to be more compact and stable with higher free binding energy (−67.84 ± 0.50 kJ/mol) than PLA2-phloroglucinol complex (−77.17 ± 0.52 kJ/mol), based on MM-PBSA analysis. The sialidase-phloroglucinol complex had a single hydrogen bond interaction with Ser453 while none was observed for the PLA2-phloroglucinol complex. In conclusion, phloroglucinol showed moderate trypanostatic activity with great potential in ameliorating some of the parasite-induced pathologies and its anti-anemic effects might be linked to inhibition of sialidase rather than PLA2.

scholarly journals In silico identification of novel chemical compounds with anti-TB potential for the inhibition of InhA and EthR from Mycobacterium tuberculosis

2020 ◽  
Author(s):  
Sajal Kumar Halder ◽  
Fatiha Elma
Keyword(s):  
Molecular Dynamics ◽  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Chemical Compounds ◽  
Dynamics Simulation ◽  
Health Concern ◽  
Radius Of Gyration

ABSTRACTTuberculosis (TB) continuously pose a major public health concern around the globe, with a mounting death toll of approximately 1.4 million in 2019. The reduced bioavailability, increased toxicity and resistance of several first-line and second-line anti-TB drugs such as isoniazid, ethionamide have necessitated the search for new medications. In this research, we have identified several novel chemical compounds with anti-TB properties using various computational tools like molecular docking analysis, drug-likeness evaluation, ADMET profiling, P450 site of metabolism prediction and molecular dynamics simulation study. This study involves fifty drug-like compounds with antibacterial activity that inhibit InhA and EthR involved in the synthesis of one of the major lipid components, mycolic acid, which is crucial for the viability of Mycobacterium tuberculosis. Among these fifty compounds, 3-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-N-(2-methylphenyl) piperidine-1-carboxamide (C22) and 5-(4-Ethyl-phenyl)-2-(1H-tetrazol-5-ylmethyl)-2H-tetrazole (C29) were found to pass the two-step molecular docking, P450 site of metabolism prediction and pharmacokinetics filtering analysis successfully. Their binding stability for target proteins have been evaluated through RMSD, RMSF, Radius of gyration analysis from 10 ns Molecular Dynamics Simulation (MDS) run. Our identified drugs could be a capable therapeutic for Tuberculosis drug discovery, having said that more in vitro and in vivo testing is required to justify their potential as novel drug and mode of action.

scholarly journals Preliminary Study on the Effect of Quinolone against Rec A Protein for the Possible Role in the Treatment of Tuberculosis through Molecular Docking

2021 ◽  
Vol 9 (VII) ◽  
pp. 227-232
Author(s):  
Priyanka Gautam
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Chronic Disease ◽  
In Vivo Studies ◽  
Online Database ◽  
Docking Method ◽  
Preliminary Study ◽  
Molecular Docking Method

Tuberculosis is a type of ancient, chronic disease which affects humans and caused by Mycobacterium tuberculosis. They affect the lungs and other organs. The treatment is curable but in some cases it is fatal if not treated properly. The molecular docking method was used to see the interaction of the protein with the ligand. Thus, molecular docking was used to analyse the Rec A (PDB ID 1U94) target protein with their known type of ligand by using molecular docking tools. The Rec A (PDB ID 1U94) structure of protein was downloaded through online database. The best ligand after molecular docking was Quinolone, which may act as a drug after in vitro and in vivo studies.

scholarly journals Molecular Docking and Drug-Likeness for the Identification of Inhibitory Action of Acetogenins from Annona muricata as Potential Anticancer against Hypoxia Inducible Factor 1 Alpha

2018 ◽  
Vol 11 (3) ◽  
pp. 1301-1307
Author(s):  
Supri I. Handayani ◽  
Rahmiati Rahmiati ◽  
Lisnawati Rahmadi ◽  
Rosmalena Rosmalena ◽  
Vivitri D. Prasasty
Keyword(s):  
Molecular Docking ◽  
Hypoxia Inducible Factor ◽  
Binding Energies ◽  
Binding Modes ◽  
Annona Muricata ◽  
Chemical Structures ◽  
Hypoxia Inducible Factor 1 ◽  
Human Cancers

Hypoxia inducible factor 1 alpha (HIF-1α) regulates cell growth and differentiation which is implicated in human cancers. HIF-1α activates its cascade carcinogenesis mechanism in cancer cells. It is well-understood that signaling is initiated by HIF-1α receptor. Overexpression of HIF-1α is associated with several different human cancers, including breast cancer, lung cancer and colon cancer. Thus, HIF-1α becomes potential target of therapeutic approach in developing HIF-1α inhibitors. The aim of this research is to investigate potential inhibitors which are known as Acetogenins (AGEs) isolated from Annona muricata against HIF-1α. In order to achieve this goal, chemical structures of all compounds were retrieved from PubChem database. Molecular docking was performed by AutoDock Vina program and the resulting binding modes were analyzed with AutoDock Tools program. Among all the compounds, murihexocin A showed the best binding modes compared to other two inhibitors based on the lowest binding energies (LBE = -7.9 kcal/mol) as high as gefitinib. This was indicating that murihexocin A has favorable interaction with the essential amino acid residues at catalytic site of HIF-1α. Drug-likeness calculation of AGEs were also performed. These in silico results could be beneficial as a compound model for further studies in-vitro and in-vivo.

Potential Bioactive glycosylated flavonoids as SARS-CoV-2 Main protease Inhibitors: A molecular Docking Study

2020 ◽  
Author(s):  
sabri ahmed cherrak ◽  
merzouk hafida ◽  
mokhtari soulimane nassima
Keyword(s):  
Molecular Docking ◽  
Data Bank ◽  
Docking Study ◽  
Docking Studies ◽  
Molecular Docking Study ◽  
Chemical Structures ◽  
In Vivo Experiments ◽  
Main Protease

A novel (COVID-19) responsible of acute respiratory infection closely related to SARS-CoV has recently emerged. So far there is no consensus for drug treatment to stop the spread of the virus. Discovery of a drug that would limit the virus expansion is one of the biggest challenges faced by the humanity in the last decades. In this perspective, testing existing drugs as inhibitors of the main COVID-19 protease is a good approach.Among natural phenolic compounds found in plants, fruit, and vegetables; flavonoids are the most abundant. Flavonoids, especially in their glycosylated forms, display a number of physiological activities, which makes them interesting to investigate as antiviral molecules.The flavonoids chemical structures were downloaded from PubChem and protease structure 6lu7 was from the Protein Data Bank site. Molecular docking study was performed using AutoDock Vina. Among the tested molecules Quercetin-3-O-rhamnoside showed the highest binding affinity (-9,7 kcal/mol). Docking studies showed that glycosylated flavonoids are good inhibitors for the covid-19 protease and could be further investigated by in vitro and in vivo experiments for further validation.

Sign in / Sign up

Export Citation Format

Share Document