scholarly journals Design of New Quinazoline Derivative as EGFR (Epidermal Growth Factor Receptor) Inhibitor through Molecular Docking and Dynamics Simulation

2020 ◽  
Vol 21 (1) ◽  
pp. 201
Author(s):  
Herlina Rasyid ◽  
Bambang Purwono ◽  
Harno Dwi Pranowo
Keyword(s):  
Molecular Docking ◽  
Growth Factor Receptor ◽  
Pharmacophore Model ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Energy Calculation ◽  
Egfr Inhibitor ◽  
Lead Compound ◽  
Quinazoline Derivative ◽  
Hydrogen Bond Interaction

Erlotinib, Afatinib, and WZ4002 are quinazoline derivative compounds and classified as first, second, and third-generation EGFR inhibitor. All inhibitors have been given directly to cancer patients for many years but find some resistance. These three compounds are candidates as the lead compound in designing a new inhibitor. This work aims to design a new potential quinazoline derivative as an EGFR inhibitor focused on the molecular docking result of the lead compound. The research method was started in building a pharmacophore model of the lead compound then used to design a new potential inhibitor by employing the AutoDock 4.2 program. Molecular dynamics simulation evaluates the interaction of all complexes using the Amber15 program. There are three new potential compounds (A1, B1, and C1) whose hydrogen bond interaction in the main catalytic area (Met769 residue). The Molecular Mechanics Generalized Born Surface Area (MM-GBSA) binding energy calculation shows that B1 and C1 compounds have lower binding energies than erlotinib as a positive control, which indicates that B1 and C1 are potential as EGFR inhibitor.

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 MOLECULAR DOCKING OF HYRTIMOMINE A-K FROM MARINE SPONGE HYRTIOS SPP. AS ANTICANCER TARGET OF PHOSPHOINOSITIDE-DEPENDENT KINASE 1

2019 ◽  
pp. 130-135
Author(s):  
RAMA ADIGA
Keyword(s):  
Molecular Docking ◽  
Target Selection ◽  
Binding Energies ◽  
Lead Compound ◽  
Hydrogen Bond Interaction ◽  
Anticancer Properties ◽  
Pharmacokinetic Properties ◽  
Selection For ◽  
New Compounds ◽  
Phosphoinositide Dependent Kinase

Objective: The hyrtimomine A-K class of indole-based compounds extracted from Hyrtios spp. of sponges from the sea has not been studied for their anticancer properties. Phosphoinositide-dependent kinase 1 (PDK1) is a master regulator of many types of cancer. Compounds currently targeting PDK1 are currently of poor specificity and solubility. Hence, molecular docking to look for new compounds inhibiting PDK1 from the marine environment was carried out. Methods: Target selection for ligands hyrtimomine A-K was done using PharmMapper tool. Molecular docking was done using iGEMDOCK 2.1, a generic evolutionary method of docking. Site moiety mapping was done in SimMap to extract the anchor preference of the top hits. Comparison of ligand binding energies, pharmacokinetic properties with lead compound BX-517 was carried out. Results: Hyrtimomine B, C, D, and G were top hits using iGEMDOCK. The highest score was obtained for hyrtimomine C. Van der Waals interaction at T222 and V96 and hydrogen bond interaction at K111 determined pocket stability. The solubility properties of the compound showed higher score for hyrtimomine C. The conserved features of hyrtimomine C were then compared with the crystal structure of lead compound (BX-517, which was not developed further due to poor solubility and bioavailability). The pharmacokinetic properties of hyrtimomine C were superior to BX-517 and had better solubility and drug-likeness score, hence, may be a candidate structure for drug development. Conclusion: The unique azapeno indole structure of hyrtimomine C highlighted the mode of binding and residues in binding site.

scholarly journals Ligand based 3D-QSAR pharmacophore, molecular docking and ADME to identify potential fibroblast growth factor receptor 1 inhibitors

2020 ◽  
Author(s):  
Zizhong Tang ◽  
Lu Huang ◽  
Xiaoli Fu ◽  
Haoxiang Wang ◽  
Biao Tang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Growth Factor Receptor ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Protein Database ◽  
Hydrogen Bond Interaction ◽  
Stromal Microenvironment ◽  
Good Ability ◽  
Zinc Database ◽  
Crystal Complex

Abstract Background The FGF/FGFR system may affect tumor cells and stromal microenvironment through autocrine and paracrine stimulation, thereby significantly promoting oncogene transformation and tumor growth. Abnormal expression of FGFR1 in cells is considered to be the main cause of tumorigenesis and a potential target for the treatment of cancer.Methods The known inhibitors were collected to construct 3D-QSAR pharmacophore model, which was verified by cost analysis, test set validation and Fischer test. Virtual screening of zinc database based on pharmacophore was carried out. FGFR1 crystal complex was downloaded from the protein database to dock with the compound. Finally, the absorption, distribution, metabolism and excretion (ADME) characteristics and toxicity of a series of potential inhibitors were studied.Results It was found that the constructed pharmacophore had a good ability to predict the activity. 2763 compounds in the database could hit well and the predicted activity value was less than 1 µM. Through molecular docking, we found that six compounds can bind to protein stably and inhibit the activity of FGFR1 through hydrogen bond interaction. In ADME and toxicity studies, we have successfully screened out a compound with a new structure scaffold, and found that it has good oral bioavailability and non-toxic.Conclusions This study screened out a new potential drug for cancer treatment, which can be further studied to explore its better therapeutic effect.

scholarly journals Screening marine algae metabolites as high-affinity inhibitors of SARS-CoV-2 main protease (3CLpro): an in silico analysis to identify novel drug candidates to combat COVID-19 pandemic

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Ghazala Muteeb ◽  
Adil Alshoaibi ◽  
Mohammad Aatif ◽  
Md. Tabish Rehman ◽  
M. Zuhaib Qayyum
Keyword(s):  
Hydrophobic Interactions ◽  
In Silico Analysis ◽  
Salt Bridge ◽  
Competitive Inhibitor ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Energy Calculation

AbstractThe recent dissemination of SARS-CoV-2 from Wuhan city to all over the world has created a pandemic. COVID-19 has cost many human lives and created an enormous economic burden. Although many drugs/vaccines are in different stages of clinical trials, still none is clinically available. We have screened a marine seaweed database (1110 compounds) against 3CLpro of SARS-CoV-2 using computational approaches. High throughput virtual screening was performed on compounds, and 86 of them with docking score <  − 5.000 kcal mol−1 were subjected to standard-precision docking. Based on binding energies (< − 6.000 kcal mol−1), 9 compounds were further shortlisted and subjected to extra-precision docking. Free energy calculation by Prime-MM/GBSA suggested RC002, GA004, and GA006 as the most potent inhibitors of 3CLpro. An analysis of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of RC002, GA004, and GA006 indicated that only RC002 (callophysin A, from red alga Callophycus oppositifolius) passed Lipinski’s, Veber’s, PAINS and Brenk’s filters and displayed drug-like and lead-like properties. Analysis of 3CLpro-callophysin A complex revealed the involvement of salt bridge, hydrogen bonds, and hydrophobic interactions. callophysin A interacted with the catalytic residues (His41 and Cys145) of 3CLpro; hence it may act as a mechanism-based competitive inhibitor. Docking energy and docking affinity of callophysin A towards 3CLpro was − 8.776 kcal mol−1 and 2.73 × 106 M−1, respectively. Molecular dynamics simulation confirmed the stability of the 3CLpro-callophysin A complex. The findings of this study may serve as the basis for further validation by in vitro and in vivo studies.

scholarly journals Discovery of Small Molecules that Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 269 ◽  
Author(s):  
Shailima Rampogu ◽  
Ayoung Baek ◽  
Chanin Park ◽  
Shraddha Parate ◽  
Saravanan Parameswaran ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Molecular Docking ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Pharmacophore Model ◽  
Docking Studies ◽  
Vascular Endothelial ◽  
Molecular Docking Studies ◽  
Angiogenic Inhibitors ◽  
Endothelial Growth Factor

Angiogenesis is defined as the formation of new blood vessels and is a key phenomenon manifested in a host of cancers during which tyrosine kinases play a crucial role. Vascular endothelial growth factor receptor-2 (VEGFR-2) is pivotal in cancer angiogenesis, which warrants the urgency of discovering new anti-angiogenic inhibitors that target the signalling pathways. To obtain this objective, a structure-based pharmacophore model was built from the drug target VEGFR-2 (PDB code: 4AG8), complexed with axitinib and was subsequently validated and employed as a 3D query to retrieve the candidate compounds with the key inhibitory features. The model was escalated to molecular docking studies resulting in seven candidate compounds. The molecular docking studies revealed that the seven compounds displayed a higher dock score than the reference-cocrystallised compound. The GROningen MAchine for Chemical Simulations (GROMACS) package guided molecular dynamics (MD) results determined their binding mode and affirmed stable root mean square deviation. Furthermore, these compounds have preserved their key interactions with the residues Glu885, Glu917, Cys919 and Asp1046. The obtained findings deem that the seven compounds could act as novel anti-angiogenic inhibitors and may further assist as the prototype in designing and developing new inhibitors.

Discovery of vascular endothelial growth factor receptor tyrosine kinase inhibitors by quantitative structure–activity relationships, molecular dynamics simulation and free energy calculation

RSC Advances ◽  
2016 ◽  
Vol 6 (42) ◽  
pp. 35402-35415 ◽  
Author(s):  
Juan Wang ◽  
Mao Shu ◽  
Xiaorong Wen ◽  
Yuanliang Wang ◽  
Yuanqiang Wang ◽  
...  
Keyword(s):  
Rational Design ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Dynamics Simulation ◽  
Energy Calculation ◽  
Vascular Endothelial ◽  
Structure Activity ◽  
Quantitative Structure Activity Relationships ◽  
Combined Strategy ◽  
Endothelial Growth Factor

Employing the combined strategy to understand the features of KDR–ligands complexes, and provide a basis for rational design of inhibitors.

Discovery of potential negative allosteric modulators of mGluR5 from natural products using pharmacophore modeling, molecular docking, and molecular dynamics simulation studies

2015 ◽  
Vol 93 (11) ◽  
pp. 1199-1206 ◽  
Author(s):  
Ludi Jiang ◽  
Yong Li ◽  
Liansheng Qiao ◽  
Xi Chen ◽  
Yusu He ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Natural Products ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Dynamics Simulation ◽  
Allosteric Modulators ◽  
Subtype Selectivity ◽  
Wide Range

mGluR5, which belongs to the G-protein-coupled receptor superfamily, is believed to be associated with many human diseases, such as a wide range of neurological disorders, gastroesophageal reflux disease, and cancer. Comparing with compounds that target on the orthosteric binding site, significant roles have been established for mGluR5 negative allosteric modulators (NAMs) due to their higher subtype selectivity and more suitable pharmacokinetic profiles. Nevertheless, to date, none of them have come to market for various reasons. In this study, a 3D quantitative pharmacophore model was generated by using the HypoGen module in Discovery Studio 4.0. With several validation methods ultilized, the optimal pharmacophore model Hypo2 was selected to discover potential mGluR5 NAMs from natural products. Two hundred and seventeen potential NAMs were obtained after being filtered by Lipinski’s rule (≥4). Then, molecular docking was used to refine the pharmacophore-based screening results and analyze the binding mode of NAMs and mGluR5. Three compounds, aglaiduline, 5-O-ethyl-hirsutanonol, and yakuchinone A, with good ADMET properties, acceptable Fit value and estimated value, and high docking score, were reserved for a molecular dynamics simulation study. All of them have stability of ligand binding. From our computational results, there might exhibit drug-like negative allosteric moderating effects on mGluR5 in these natural products. This work provides a reliable method for discovering mGluR5 NAMs from natural products.

scholarly journals Ligand Based 3D-QSAR Pharmacophore, Molecular Docking and Adme to Identify Potential Fibroblast Growth Factor Receptor 1 Inhibitors 

2020 ◽  
Author(s):  
Zizhong Tang ◽  
Lu Huang ◽  
Xiaoli Fu ◽  
Haoxiang Wang ◽  
Biao Tang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Growth Factor Receptor ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Drug Carriers ◽  
Therapeutic Effects ◽  
Lipinski’S Rule ◽  
Discovery Studio ◽  
Zinc Database

Abstract The FGF/FGFR system may affect tumor cells and stromal microenvironment through autocrine and paracrine stimulation, thereby significantly promoting oncogene transformation and tumor growth. Abnormal expression of FGFR1 in cells is considered to be the main cause of tumorigenesis and a potential target for the treatment of cancer. In this study, a combination of structure-based drug carriers and molecular docking-based virtual screening was used to screen new potential FGFR1 inhibitors. Twenty-one known inhibitors were collected as training sets to establish a 3D-QSAR pharmacophore model, and cost analysis, test set validation, and Fischer randomization test were used to validate the efficiency of the pharmacophore model. In Accelrys Discovery Studio 2016, the zinc database was filtered by Lipinski's Rule of Five and SMART's filtration. Then, Hypo01 was used for virtual screening of ZINC database. Compounds with predicted activity values less than 1 μM were molecularly docked with FGFR1 protein crystals, the docking results were observed, and the interaction between compounds and targets was studied. The absorption, distribution, metabolism and excretion (ADME) and toxicity of potential inhibitors were studied, and a compound with new structural scaffolds were obtained. It could be further studied to explore their better therapeutic effects.

scholarly journals Prediction of Drug Potencies of BACE1 Inhibitors: A Molecular Dynamics Simulation and MM_GB(PB)SA Scoring

2020 ◽  
Author(s):  
Mazen Hamed
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Electrostatic Interactions ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Energy Calculation ◽  
Brain Disorder ◽  
Kd Values

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder. One of the important therapeutic approaches of AD is the inhibition of &beta;‐site APP cleaving enzyme‐1 (BACE1). This enzyme plays a central role in the synthesis of the pathogenic &beta;-amyloid peptides (A&beta;) in Alzheimer's disease. A group of potent BACE1 inhibitors with known x-ray structures (PDB ID 5i3X, 5i3Y, 5iE1, 5i3V, 5i3W, 4LC7, 3TPP) were studied by molecular dynamics simulation and binding energy calculation employing MM_GB(PB)SA. The calculated binding energies gave Kd values 0.139 &micro;M, 1.39 nM, 4.39 mM, 24.3 nM, 1.39 mM, 29.13 mM and 193.07 nM, respectively. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. The Kd values were compared with experimental values, the structures were discussed in view of the energy contributions to binding. Drug likeness of these inhibitors is also discussed. Accommodation of ligands in the catalytic site of BACE1 is discussed depending on the type of fragment involved in each structure. Molecular dynamics (MD) simulations and energy studies were used to explore the recognition of the selected BACE1 inhibitors by Asp 32, Asp228 and the hydrophobic flap. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, &pi;-&pi; and Van der Waals interactions with the amino acid residues located inside the catalytic cavity. Interactions with the ligands show a similar binding mode with BACE1. These results help to rationalize the design of selective BACE1 inhibitors.

scholarly journals Molecular Docking and Dynamics Simulation Study of Hyrtios erectus Isolated Scalarane Sesterterpenes as Potential SARS-CoV-2 Dual Target Inhibitors

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 389
Author(s):  
Sameh S. Elhady ◽  
Reda F. A. Abdelhameed ◽  
Rania T. Malatani ◽  
Abdulrahman M. Alahdal ◽  
Hanin A. Bogari ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Md Simulation ◽  
Protein Complexes ◽  
Antiviral Agents ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Main Protease ◽  
Simulation Parameters ◽  
Molecular Docking And Dynamics ◽  
Dual Target

Presently, the world is under the toll of pandemic coronavirus disease-2019 (COVID-19) outbreak caused by SARS-CoV-2. Lack of effective and safe therapeutics has stressed the scientific community for developing novel therapeutics capable of alleviating and stopping this pandemic. Within the presented study, molecular docking, ADME properties and all-atom molecular dynamic (MD) simulation, along with two standard antiviral agents (lopinavir and benzopurpurin-4B), were applied to investigate 15 scalaranes sesterterpenes natural compounds, purified from the Red Sea marine sponge Hyrtios erectus, as potential COVID-19 dual-target inhibitors. Following multi-step docking within COVID-19 main protease and Nsp15 endoribonuclease cavities, nine promising drug-like compounds exhibited higher docking scores as well as better interactions with the target’s crucial residues than those of reference ligands. Compounds 2, 6, 11, and 15, were predicted to simultaneously subdue the activity of the two COVID-19 targets. Dynamics behavior of the best-docked molecules, compounds 15 and 6, within COVID-19 target pockets showed substantial stability of ligand-protein complexes as presented via several MD simulation parameters. Furthermore, calculated free-binding energies from MD simulation illustrated significant ligand’s binding affinity towards respective target pockets. All provided findings supported the utility of scalarane-based sesterterpenes, particularly compounds 15 and 6, as promising lead candidates guiding the development of effective therapeutics against SARS-CoV-2.

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