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

10.26434/chemrxiv.12480464 ◽

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

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 Mycobacterium tuberculosis (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.

Download Full-text

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

10.26434/chemrxiv.12505187.v1 ◽

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

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 Mycobacterium tuberculosis (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+ 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 in vivo and in vitro validation.

Download Full-text

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

10.26434/chemrxiv.12505187 ◽

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

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 Mycobacterium tuberculosis (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+ 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 in vivo and in vitro validation.

Download Full-text

In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

10.26434/chemrxiv.12480434.v1 ◽

2020 ◽

Author(s):

Sahar Qazi ◽

Mustafa Alhaji Isa ◽

Adam Mustapha ◽

Khalid Raza ◽

Ibrahim Alkali Allamin ◽

...

Keyword(s):

Molecular Docking ◽

Severe Acute Respiratory Syndrome ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

Anacardium Occidentale ◽

Upper Respiratory Tract ◽

Ligand Complex ◽

In Silico Docking ◽

Main Protease

The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of Zingiber offinale and Anacardium occidentale using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of Zingiber offinale and the leaves of Anacardium occidentale. These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), Pan-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907).

Download Full-text

In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

10.26434/chemrxiv.12480434 ◽

2020 ◽

Author(s):

Sahar Qazi ◽

Mustafa Alhaji Isa ◽

Adam Mustapha ◽

Khalid Raza ◽

Ibrahim Alkali Allamin ◽

...

Keyword(s):

Molecular Docking ◽

Severe Acute Respiratory Syndrome ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

Anacardium Occidentale ◽

Upper Respiratory Tract ◽

Ligand Complex ◽

In Silico Docking ◽

Main Protease

The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of Zingiber offinale and Anacardium occidentale using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of Zingiber offinale and the leaves of Anacardium occidentale. These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), Pan-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907).

Download Full-text

Study of Caspase 8 Inhibition for the Management of Alzheimer’s Disease: A Molecular Docking and Dynamics Simulation

Molecules ◽

10.3390/molecules25092071 ◽

2020 ◽

Vol 25 (9) ◽

pp. 2071

Author(s):

Syed Sayeed Ahmad ◽

Meetali Sinha ◽

Khurshid Ahmad ◽

Mohammad Khalid ◽

Inho Choi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Docking ◽

Md Simulation ◽

Simulation Analysis ◽

Dynamics Simulation ◽

Caspase 8 ◽

Amino Acid Residues ◽

The Stability ◽

Molecular Docking And Dynamics

Alzheimer’s disease (AD) is the most common type of dementia and usually manifests as diminished episodic memory and cognitive functions. Caspases are crucial mediators of neuronal death in a number of neurodegenerative diseases, and caspase 8 is considered a major therapeutic target in the context of AD. In the present study, we performed a virtual screening of 200 natural compounds by molecular docking with respect to their abilities to bind with caspase 8. Among them, rutaecarpine was found to have the highest (negative) binding energy (−6.5 kcal/mol) and was further subjected to molecular dynamics (MD) simulation analysis. Caspase 8 was determined to interact with rutaecarpine through five amino acid residues, specifically Thr337, Lys353, Val354, Phe355, and Phe356, and two hydrogen bonds (ligand: H35-A: LYS353:O and A:PHE355: N-ligand: N5). Furthermore, a 50 ns MD simulation was conducted to optimize the interaction, to predict complex flexibility, and to investigate the stability of the caspase 8–rutaecarpine complex, which appeared to be quite stable. The obtained results propose that rutaecarpine could be a lead compound that bears remarkable anti-Alzheimer’s potential against caspase 8.

Download Full-text

Homology Modelling and Molecular Docking Studies of Selected Substituted Benzo[d]imidazol-1-yl)methyl)benzimidamide Scaffolds on Plasmodium falciparum Adenylosuccinate Lyase Receptor

Bioinformatics and Biology Insights ◽

10.1177/1177932219865533 ◽

2019 ◽

Vol 13 ◽

pp. 117793221986553 ◽

Cited By ~ 1

Author(s):

Gbolahan O Oduselu ◽

Olayinka O Ajani ◽

Yvonne U Ajamma ◽

Benedikt Brors ◽

Ezekiel Adebiyi

Keyword(s):

Plasmodium Falciparum ◽

Molecular Docking ◽

In Silico ◽

Homology Modelling ◽

3D Structure ◽

Docking Studies ◽

Binding Energies ◽

Benzimidazole Derivatives ◽

Adenylosuccinate Lyase ◽

In Silico Admet

Plasmodium falciparum adenylosuccinate lyase ( PfADSL) is an important enzyme in purine metabolism. Although several benzimidazole derivatives have been commercially developed into drugs, the template design as inhibitor against PfADSL has not been fully explored. This study aims to model the 3-dimensional (3D) structure of PfADSL, design and predict in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) of 8 substituted benzo[ d]imidazol-1-yl)methyl)benzimidamide compounds as well as predict the potential interaction modes and binding affinities of the designed ligands with the modelled PfADSL. PfADSL 3D structure was modelled using SWISS-MODEL, whereas the compounds were designed using ChemDraw Professional. ADMET predictions were done using OSIRIS Property Explorer and Swiss ADME, whereas molecular docking was done with AutoDock Tools. All designed compounds exhibited good in silico ADMET properties, hence can be considered safe for drug development. Binding energies ranged from −6.85 to −8.75 kcal/mol. Thus, they could be further synthesised and developed into active commercial antimalarial drugs.

Download Full-text

MOLECULAR DOCKING STUDIES FOR THE COMPARATIVE ANALYSIS OF DIFFERENT BIOMOLECULES TO TARGET HYPOXIA INDUCIBLE FACTOR-1α

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2017v9i4.19505 ◽

2017 ◽

Vol 9 (4) ◽

pp. 83 ◽

Cited By ~ 1

Author(s):

Niraj Kumar Jha ◽

Pravir Kumar

Keyword(s):

Molecular Docking ◽

In Silico ◽

Hypoxia Inducible Factor ◽

3D Structure ◽

Amyloid Β ◽

Docking Studies ◽

Therapeutic Window ◽

Hypoxic Exposure ◽

Amyloid Β Protein ◽

Lipinski’S Rule

Objective: Hypoxia plays a significant role in governing many vital signalling molecules in the central nervous system (CNS). Hypoxic exposure has also been depicted as a stimulus for oxidative stress, increase in lipid peroxidation, DNA damage, blood-brain dysfunction, impaired calcium (Ca2+) homoeostasis and agglomeration of oxidized biomolecules in neurons, which act as a novel signature in diverse neurodegenerative and oncogenic processes. On the contrary, the presence of abnormally impaired expression of HIF-1α under hypoxic insult could serve as an indication of the existence of tumors and neuronal dysfunction as well. For instance, under hypoxic stress, amyloid-β protein precursor (AβPP) cleavage is triggered due to the higher expression of HIF-1α and thus leads to synaptic loss. The objective of this research is to perform comparative studies of biomolecules in regulating HIF-1α activity based on in silico approaches that could establish a potential therapeutic window for the treatment of different abnormalities associated with impaired HIF-1α.Methods: We employed various in silico methods such as drug-likeness parameters namely Lipinski filter analysis, Muscle tool, SWISS-MODEL, active site prediction, Auto Dock 4.2.1 and LigPlot1.4.5for molecular docking studies.Results: 3D structure of HIF-1α was generated and Ramachandran plot obtained for quality assessment. RAMPAGE displayed 99.5% of residues in the most favoured regions. 0% residues in additionally allowed and 0.5% disallowed regions of the HIF-1α protein. Further, initial screenings of the molecules were done based on Lipinski’s rule of five. Cast P server used to predict the ligand binding site suggests that this protein can be utilised as a potential drug target. Finally, we have found Naringenin to be most effective amongst three biomolecules in modulating HIF-1α based on minimum inhibition constant, Ki and highest negative free energy of binding with the maximum interacting surface area during docking studies.Conclusion: The present study outlines the novel potential of Biomolecules in regulating HIF-1α activity for the treatment of different abnormalities associated with impaired HIF-1α.

Download Full-text

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

10.26434/chemrxiv.12498155.v1 ◽

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 Mycobacterium tuberculosis (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.”

Download Full-text

Identification of Potent Inhibitors of ATP Synthase Subunit C (AtpE) from Mycobacterium Tuberculosis Using in Silico Approach

10.26434/chemrxiv.12480452 ◽

2020 ◽

Author(s):

Dr. Mustafa Alhaji Isa

Keyword(s):

Mycobacterium Tuberculosis ◽

Binding Energy ◽

Atp Synthase ◽

Md Simulation ◽

Binding Energies ◽

Model Structure ◽

Generalized Born ◽

Subunit C ◽

Docking Analysis ◽

Pubchem Database

ATP synthase subunit c (AtpE) is an enzyme that catalyzes the production of ATP from ADP in the presence of sodium or proton gradient from Mycobacterium tuberculosis (MTB). This enzyme considered an essential target for drug design and its shares the same pathway with the target of Isoniazid. Thus, this enzyme would serve as an alternative target of the Isoniazid. The 3D model structure of the AtpE was constructed based on the principle of the homology modeling using the Modeller9.16. The developed model was subjected to the energy minimization and refinement using molecular dynamic (MD) simulation. The minimized model structure was searched against Zinc and PubChem database to determine ligands that bind to the enzyme with minimum binding energy using RASPD and PyRx tool. A total of 4776 compounds capable of binding to AtpE with minimum binding energies were selected. These compounds further screened for physicochemical properties (Lipinski rule of five). All the compounds that possessed the desirable properties selected and used for molecular docking analysis. Five (5) compounds with minimum binding energies ranged between ─8.69, and ─8.44kcal/mol, less than the free binding energy of ATP were selected. These compound further screened for the absorption, distribution, metabolism, excretion, and toxicity (ADME and toxicity) properties. Of the five compounds, three (ZINC14732869, ZINC14742188, and ZINC12205447) fitted all the ADME and toxicity properties and subjected to MD simulation and Molecular Mechanics Generalized Born and Surface Area (MM-GBSA) analyses. The results indicated that the ligands formed relatively stable complexes and had free binding energies, less than the binding energy of the ATP. Therefore, these ligands considered as prospective inhibitors of MTB after successful experimental validation

Download Full-text