scholarly journals Computational Study on Novel Natural Inhibitors Targeting c-MET

2021 ◽  
Author(s):  
Junliang Ge ◽  
Bo Wu ◽  
Wenzhuo Yang ◽  
Sheng Zhong ◽  
Yuanyuan Hou ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Affinity ◽  
Computational Study ◽  
Developmental Toxicity ◽  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Drug Candidates ◽  
Zinc Database ◽  
The Stability ◽  
Dynamics Simulations

Abstract Object This study was designed to select ideal lead compounds and preclinical drug candidates with inhibitory effect on c-MET from the drug library (ZINC database).Methods A battery of computer-aided virtual techniques were used to identify possible inhibitors of c-MET. LibDock is applied for structure-based screening followed by ADME (absorption, distribution, metabolic, excretion) and toxicity prediction. Molecular docking was conducted to confirm the binding affinity mechanism between the ligand and c-MET Molecular dynamics simulations were used to assess the stability of ligand-c-MET complexes.Results Two new natural compounds ZINC000005879645 and ZINC000002528509 were found to bind to c-MET in ZINC database, showing higher binding affinity. In addition, they were predicted to have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6. Molecular dynamics simulation shows that ZINC000005879645 and ZINC000002528509 have more favorable potential energies with c-MET, which could exist stably in the natural environment.Conclusion This study suggests that ZINC000005879645 and ZINC000002528509 are ideal latent inhibitors of c-MET targeting. As drug candidates, these two compounds have great security and important implications for the design and improvement of c-MET target drugs.

scholarly journals Novel Natural Inhibitors Targeting AKT1 by Computational Study

2021 ◽  
Author(s):  
Bo Wu ◽  
Wenzhuo Yang ◽  
Zhiyun Zhang ◽  
Gaojing Dou ◽  
Xiaye Lv ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Computational Study ◽  
Developmental Toxicity ◽  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Drug Candidates ◽  
Receptor Complexes ◽  
Zinc Database ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Abstract Object: This study was designed to screen ideal lead compounds and drug candidates with an inhibitory effect on AKT1 from the drug library (ZINC database).Methods: A battery of computer-aided virtual techniques were used to identify potential inhibitors of AKT1. LibDock is used for structure-based screening followed by ADME (absorption distribution, metabolic excretion) and toxicity prediction. Molecular dynamics simulations were used to evaluate the stability of ligand-receptor complexes.Results: Two new natural compounds ZINC000049872065 and ZINC000021992902 were found to bind to AKT1 in the ZINC database, showing a higher binding affinity. Also, they were predicted to have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6. Molecular dynamics simulation shows that ZINC000049872065 and ZINC000021992902 have more favorable potential energies with AKT1, which can exist stably in the natural environment.Conclusion: This study suggests that ZINC000049872065 and ZINC000021992902 are ideal potential inhibitors of AKT1 targeting. These compounds are safe drug candidates and have important implications for the design and improvement of C-MET target drugs.

scholarly journals Molecular Modeling of Some Benzodiazole Derivatives with EGFR Protein 1M17

2020 ◽  
pp. 84-95
Author(s):  
A. S. Sony ◽  
Xavier Suresh
Keyword(s):  
Molecular Dynamics ◽  
Molecular Modeling ◽  
Molecular Dynamics Simulation ◽  
Binding Affinity ◽  
Simulation Study ◽  
Docking Studies ◽  
Dynamics Simulation ◽  
Ligand Complex ◽  
Drug Candidates ◽  
The Stability

Aims: To study the anticancer potential of benzodiazole derivatives using molecular modeling studies. Study Design: Molecular Dynamics simulation study. Place and Duration of Study: Sathyabama Institute of Science and Technology (SIST), Chennai, between June 2020 and August 2020. Methodology: We studied the anticancer potential of benzodiazole derivatives using molecular modeling. Docking studies of the ligands with EGFR protein 1M17 was carried out using AutoDock.Molecular Dynamics simulation study was carried out using Playmolecule was used to verify the stability of the protein-ligand complex. Results: Molecular docking studies showed a good binding affinity of the ligands with the protein 1m17. Benzodiazole derivative 4,6-dichloro-2-(trifluoromethyl)-1H-1,3-benzodiazole exhibited the lowest binding energy of (-6.42 kcal/mol) at the active site of EGFR (PDB code:1M17) consistent with its least inhibition coefficient (Ki =32.54 uM). Molecular dynamics simulation showed better stability of the ligand and protein complex. Conclusion: Molecular modeling study of selected benzodiazole derivatives showed a very good binding affinity to EGFR protein 1m17. MD simulation of the best-docked ligand showed that the complex was stable. Our study demonstrated that benzodiazole derivatives can be potential anticancer drug candidates

scholarly journals Computational Study on Novel Natural Inhibitors Targeting BCL2

2021 ◽  
Author(s):  
Xiaye Lv ◽  
Yuting Jiang ◽  
Xinhui Wang ◽  
Gaojing Dou ◽  
Jing Wang ◽  
...  
Keyword(s):  
Computational Study ◽  
Developmental Toxicity ◽  
B Cell Lymphoma ◽  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Lead Compounds ◽  
Toxicity Potential ◽  
Zinc Database ◽  
Potential Inhibitors ◽  
New Compounds

Abstract Object: Ideal lead compounds and candidate drugs with inhibitory effect on BCL2 were screened from ZINC database, which laid a foundation for drug development and compound improvement of drug treatment for diffuse large B-cell lymphoma (DLCBL). Methods: Identification of potential BCL2 inhibitors by computer-aided virtual screening. Libdock was applied to value 17931 compounds and top20 were selected for further analysis. Selected compounds were performed absorption, distribution, metabolism, and excretion (ADME) and toxicity prediction. The binding affinity between the selected ligands and BCL2 was confirmed by Molecular docking. Results: The new natural compounds ZINC00000255131 and ZINC00013298233 were found to bind closely with BCL2. Furthermore, they all scored lower in ames-induced mutagenicity, rodent carcinogenicity, non-developmental toxicity potential, and cytochrome P4502D6 tolerance. Molecular dynamics simulation shows that the combinations of ZINC00000255131 and ZINC00013298233 with BCL2 in the natural environment are more stable. Conclusion: Two new compounds ZINC00000255131 and ZINC00013298233 were found to be potential inhibitors of BCL2. These compounds have been proved to be safe, which is of great significance for the development and improvement of DLCBL drugs.

scholarly journals Computational study on novel natural inhibitors targeting BCL2

2021 ◽  
Vol 38 (8) ◽  
Author(s):  
Xiaye Lv ◽  
Yuting Jiang ◽  
Xinhui Wang ◽  
HaoQun Xie ◽  
Gaojing Dou ◽  
...  
Keyword(s):  
Computational Study ◽  
Developmental Toxicity ◽  
B Cell Lymphoma ◽  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Lead Compounds ◽  
Toxicity Potential ◽  
Zinc Database ◽  
Potential Inhibitors ◽  
New Compounds

AbstractIdeal lead compounds and candidate drugs with inhibitory effect on BCL2 were screened from ZINC database, which laid a foundation for drug development and compound improvement of drug treatment for diffuse large B-cell lymphoma (DLCBL). Identification of potential BCL2 inhibitors by computer-aided virtual screening. Libdock was applied to 17,931 compounds and the top 20 were selected for further analysis. Selected compounds were performed absorption, distribution, metabolism, and excretion (ADME) and toxicity prediction. The binding affinity between the selected ligands and BCL2 was confirmed by Molecular docking. The new natural compounds, ZINC00000255131 and ZINC00013298233, were found to bind closely with BCL2. Furthermore, they all scored lower in ames-induced mutagenicity, rodent carcinogenicity, non-developmental toxicity potential, and cytochrome P4502D6 tolerance. Molecular dynamics simulation shows that the combinations of ZINC00000255131 and ZINC00013298233 with BCL2 in the natural environment are more stable. Two new compounds, ZINC00000255131 and ZINC00013298233, were found to be potential inhibitors of BCL2. These compounds have been proved to be safe, which is of great significance for the development and improvement of DLCBL drugs.

Computational Discovery of SARS-CoV-2 NSP 16 Drug Candidates Based on Pharmacophore Modeling and Molecular Dynamics Simulation

2021 ◽  
Vol 20 (04) ◽  
pp. 377-390
Author(s):  
Zahra Hesari ◽  
Samaneh Zolghadri ◽  
Sajad Moradi ◽  
Mohsen Shahlaei ◽  
Elham Tazikeh-Lemeski
Keyword(s):  
Molecular Dynamics ◽  
Study Drug ◽  
Pharmacophore Modeling ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Structural Protein ◽  
Drug Candidates ◽  
Computational Discovery ◽  
Approved Drugs ◽  
Dynamics Simulations

Non-Structural Protein 16 (NSP-16) is one of the most suitable targets for discovery of drugs for corona viruses including SARS-CoV-2. In this study, drug discovery of SARS-CoV-2 nsp-16 has been accomplished by pharmacophore-based virtual screening among some analogs (FDA approved drugs) and marine natural plants (MNP). The comparison of the binding energies and the inhibition constants was determined using molecular docking method. Three compounds including two FDA approved (Ibrutinib, Idelalisib) and one MNP (Kumusine) were selected for further investigation using the molecular dynamics simulations. The results indicated that Ibrutinib and Idelalisib are oral medications while Kumusine, with proper hydrophilic and solubility properties, is an appropriate candidate for nsp-16 inhibitor and can be effective to control COVID-19 disease.

scholarly journals Identification of CDK7 Inhibitors from Natural Sources Using Pharmacoinformatics and Molecular Dynamics Simulations

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1197
Author(s):  
Vikas Kumar ◽  
Shraddha Parate ◽  
Gunjan Thakur ◽  
Gihwan Lee ◽  
Hyeon-Su Ro ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Affinity ◽  
Cost Effective ◽  
Binding Mode ◽  
Kinase Domain ◽  
Dynamics Simulation ◽  
Mode Analysis ◽  
Atp Binding Site ◽  
Dynamics Simulations

The cyclin-dependent kinase 7 (CDK7) plays a crucial role in regulating the cell cycle and RNA polymerase-based transcription. Overexpression of this kinase is linked with various cancers in humans due to its dual involvement in cell development. Furthermore, emerging evidence has revealed that inhibiting CDK7 has anti-cancer effects, driving the development of novel and more cost-effective inhibitors with enhanced selectivity for CDK7 over other CDKs. In the present investigation, a pharmacophore-based approach was utilized to identify potential hit compounds against CDK7. The generated pharmacophore models were validated and used as 3D queries to screen 55,578 natural drug-like compounds. The obtained compounds were then subjected to molecular docking and molecular dynamics simulations to predict their binding mode with CDK7. The molecular dynamics simulation trajectories were subsequently used to calculate binding affinity, revealing four hits—ZINC20392430, SN00112175, SN00004718, and SN00262261—having a better binding affinity towards CDK7 than the reference inhibitors (CT7001 and THZ1). The binding mode analysis displayed hydrogen bond interactions with the hinge region residues Met94 and Glu95, DFG motif residue Asp155, ATP-binding site residues Thr96, Asp97, and Gln141, and quintessential residue outside the kinase domain, Cys312 of CDK7. The in silico selectivity of the hits was further checked by docking with CDK2, the close homolog structure of CDK7. Additionally, the detailed pharmacokinetic properties were predicted, revealing that our hits have better properties than established CDK7 inhibitors CT7001 and THZ1. Hence, we argue that proposed hits may be crucial against CDK7-related malignancies.

scholarly journals Altering the solubility of the antibiotic candidate Nisin – a computational study

2020 ◽  
Author(s):  
Preeti Pandey ◽  
Ulrich H.E. Hansmann ◽  
Feng Wang
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Antimicrobial Activity ◽  
Broad Spectrum ◽  
Bacterial Resistance ◽  
Force Fields ◽  
Computational Study ◽  
Food Preservative ◽  
Drug Candidates ◽  
Dynamics Simulations

AbstractThe growing bacterial resistance to available antibiotics makes it necessary to look for new drug candidates. An example is a lanthionine-containing nisin, which has a broad spectrum of antimicrobial activity. While nisin is widely utilized as a food preservative, its poor solubility and low stability at physiological pH hinder its use as an antibiotic. As the solubility of nisin is controlled by the residues of the hinge region, we have performed molecular dynamics simulations of various mutants and studied their effects on nisin’s solubility. These simulations are complicated by the presence of two uncommon residues (dehydroalanine and dehydrobutyrine) in the peptide. The primary goal of the present study is to derive rules for designing new mutants that will be more soluble at physiological pH and, therefore, may serve as a basis for the future antibiotic design. Another aim of our study is to evaluate whether existing force fields can model the solubility of these amino acids accurately, in order to motivate further developments of force fields to account for solubility information.

scholarly journals Design of a New α-1-C-Alkyl-DAB Derivative Acting as a Pharmacological Chaperone for β-Glucocerebrosidase Using Ligand Docking and Molecular Dynamics Simulation

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2683 ◽  
Author(s):  
Izumi Nakagome ◽  
Atsushi Kato ◽  
Noriyuki Yamaotsu ◽  
Tomoki Yoshida ◽  
Shin-ichiro Ozawa ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Site ◽  
Binding Affinity ◽  
Gaucher Disease ◽  
Point Mutations ◽  
Dynamics Simulation ◽  
Ligand Docking ◽  
Pharmacological Chaperone ◽  
Pharmacological Chaperones ◽  
Dynamics Simulations

Some point mutations in β-glucocerebrosidase cause either improper folding or instability of this protein, resulting in Gaucher disease. Pharmacological chaperones bind to the mutant enzyme and stabilize this enzyme; thus, pharmacological chaperone therapy was proposed as a potential treatment for Gaucher disease. The binding affinities of α-1-C-alkyl 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives, which act as pharmacological chaperones for β-glucocerebrosidase, abruptly increased upon elongation of their alkyl chain. In this study, the primary causes of such an increase in binding affinity were analyzed using protein–ligand docking and molecular dynamics simulations. We found that the activity cliff between α-1-C-heptyl-DAB and α-1-C-octyl-DAB was due to the shape and size of the hydrophobic binding site accommodating the alkyl chains, and that the interaction with this hydrophobic site controlled the binding affinity of the ligands well. Furthermore, based on the aromatic/hydrophobic properties of the binding site, a 7-(tetralin-2-yl)-heptyl-DAB compound was designed and synthesized. This compound had significantly enhanced activity. The design strategy in consideration of aromatic interactions in the hydrophobic pocket was useful for generating effective pharmacological chaperones for the treatment of Gaucher disease.

scholarly journals Peptide-Ligand Binding Modeling of siRNA with Cell-Penetrating Peptides

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Alfonso T. García-Sosa ◽  
Indrek Tulp ◽  
Kent Langel ◽  
Ülo Langel
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Affinity ◽  
Cell Penetrating Peptides ◽  
Peptide Ligand ◽  
Intermolecular Hydrogen Bonds ◽  
Cell Penetrating ◽  
The Stability ◽  
Dynamics Simulations ◽  
Explicit Water

The binding affinity of a series of cell-penetrating peptides (CPP) was modeled through docking and making use of the number of intermolecular hydrogen bonds, lipophilic contacts, and the number of sp3 molecular orbital hybridization carbons. The new ranking of the peptides is consistent with the experimentally determined efficiency in the downregulation of luciferase activity, which includes the peptides’ ability to bind and deliver the siRNA into the cell. The predicted structures of the complexes of peptides to siRNA were stable throughout 10 ns long, explicit water molecular dynamics simulations. The stability and binding affinity of peptide-siRNA complexes was related to the sidechains and modifications of the CPPs, with the stearyl and quinoline groups improving affinity and stability. The reranking of the peptides docked to siRNA, together with explicit water molecular dynamics simulations, appears to be well suited to describe and predict the interaction of CPPs with siRNA.

scholarly journals Structure-Based Virtual Screening, Insilico Docking, ADME Prediction, and Molecular Dynamics Studies for Identification of Potential NMT Inhibitors Against Malaria

2021 ◽  
Author(s):  
Mohan Anbuselvam ◽  
C Ji Katherine ◽  
Anbuselvam Jeeva ◽  
Hai-Feng Ji
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Virtual Screening ◽  
Plasmodium Species ◽  
Dynamics Simulation ◽  
Therapeutic Drug ◽  
Infected Female ◽  
Adme Prediction ◽  
Zinc Database ◽  
The Stability

Abstract One of the major public health problems globally, malaria, is mainly caused protozoan parasites from the genus Plasmodium, and commonly spreads to people through the bites of infected female mosquitoes of the genus Anopheles. Strategies for treatment, prevention, and control are available for malaria but the eradication of malaria still poses great challenge due to plasmodium’s drug resistance over the past decades. Development of novel antimalarial drugs remains a significant task to protect people from malaria. N-Myristoyl transferase is responsible for the N-Myristoylation catalysis process and the survival of Plasmodium species. Thus, it is considered a therapeutic drug target in protozoans and was recently validated as a significant target for Plasmodium vivax. In this present scenario, we endeavour to identify effective NMT inhibitors to prevent the onset of malaria in the human species. Initially, the structure-based virtual screening was executed against ZINC database and four potential candidates for NMT were identified. Furthermore, the four identified compounds were subjected to ADME prediction and all the four compounds found within adequate range with predicted ADME properties. Eventually, we conducted the molecular dynamics simulation to investigate the binding stability of top three protein-ligand complexes at different time scale by employing the tool Desmond. The molecular dynamics simulation studies revealed the protein-ligand complexes were stable throughout the entire simulation. Besides, we noticed that the residues ASN 365, PHE 103 and HIS 213 of NMT were crucially involved in the formation of various intermolecular interactions, significantly contributing to the stability of protein-ligand complexes. From this computational investigation, we suggest that the three identified potential compounds are extremely useful for further lead optimization and drug development.

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