scholarly journals Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies

2020 ◽  
Vol 21 (11) ◽  
pp. 4058 ◽  
Author(s):  
Liadys Mora Lagares ◽  
Nikola Minovski ◽  
Ana Yisel Caballero Alfonso ◽  
Emilio Benfenati ◽  
Sara Wellens ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Homology Modeling ◽  
In Silico ◽  
Efflux Pump ◽  
Transmembrane Protein ◽  
Homology Model ◽  
Scoring Functions ◽  
P Glycoprotein ◽  
Ranking Scheme ◽  
Docking Calculations

The ABCB1 transporter also known as P-glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette super-family of transporters; it is a xenobiotic efflux pump that limits intracellular drug accumulation by pumping the compounds out of cells. P-gp contributes to a decrease of toxicity and possesses broad substrate specificity. It is involved in the failure of numerous anticancer and antiviral chemotherapies due to the multidrug resistance (MDR) phenomenon, where it removes the chemotherapeutics out of the targeted cells. Understanding the details of the ligand–P-gp interaction is therefore crucial for the development of drugs that might overcome the MRD phenomenon and for obtaining a more effective prediction of the toxicity of certain compounds. In this work, an in silico modeling was performed using homology modeling and molecular docking methods with the aim of better understanding the ligand–P-gp interactions. Based on different mouse P-gp structural templates from the PDB repository, a 3D model of the human P-gp (hP-gp) was constructed by means of protein homology modeling. The homology model was then used to perform molecular docking calculations on a set of thirteen compounds, including some well-known compounds that interact with P-gp as substrates, inhibitors, or both. The sum of ranking differences (SRD) was employed for the comparison of the different scoring functions used in the docking calculations. A consensus-ranking scheme was employed for the selection of the top-ranked pose for each docked ligand. The docking results showed that a high number of π interactions, mainly π–sigma, π–alkyl, and π–π type of interactions, together with the simultaneous presence of hydrogen bond interactions contribute to the stability of the ligand–protein complex in the binding site. It was also observed that some interacting residues in hP-gp are the same when compared to those observed in a co-crystallized ligand (PBDE-100) with mouse P-gp (PDB ID: 4XWK). Our in silico approach is consistent with available experimental results regarding P-gp efflux transport assay; therefore it could be useful in the prediction of the role of new compounds in systemic toxicity.

scholarly journals Multiclass Classifier for P-Glycoprotein Substrates, Inhibitors, and Non-Active Compounds

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 2006 ◽  
Author(s):  
Liadys Mora Lagares ◽  
Nikola Minovski ◽  
Marjana Novič
Keyword(s):  
In Silico ◽  
Transmembrane Protein ◽  
External Validation ◽  
Assessment Process ◽  
Classification Model ◽  
Training Set ◽  
Test Set ◽  
Active Compounds ◽  
P Glycoprotein ◽  
Validation Set

P-glycoprotein (P-gp) is a transmembrane protein that actively transports a wide variety of chemically diverse compounds out of the cell. It is highly associated with the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of drugs/drug candidates and contributes to decreasing toxicity by eliminating compounds from cells, thereby preventing intracellular accumulation. Therefore, in the drug discovery and toxicological assessment process it is advisable to pay attention to whether a compound under development could be transported by P-gp or not. In this study, an in silico multiclass classification model capable of predicting the probability of a compound to interact with P-gp was developed using a counter-propagation artificial neural network (CP ANN) based on a set of 2D molecular descriptors, as well as an extensive dataset of 2512 compounds (1178 P-gp inhibitors, 477 P-gp substrates and 857 P-gp non-active compounds). The model provided a good classification performance, producing non error rate (NER) values of 0.93 for the training set and 0.85 for the test set, while the average precision (AvPr) was 0.93 for the training set and 0.87 for the test set. An external validation set of 385 compounds was used to challenge the model’s performance. On the external validation set the NER and AvPr values were 0.70 for both indices. We believe that this in silico classifier could be effectively used as a reliable virtual screening tool for identifying potential P-gp ligands.

scholarly journals In-silico Study of the Developed Hydroxychloroquine-based ACE2 Inhibitor Molecules Against COVID-19: Molecular Modeling and Docking

2021 ◽  
Vol 11 (4) ◽  
pp. 7336-7342
Author(s):  
K. Zaher ◽  
N. E. Masango ◽  
W. Sobhi ◽  
K. E. Kanouni ◽  
A. Semmeq ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Modeling ◽  
In Silico ◽  
Viral Proteins ◽  
In Silico Study ◽  
Docking Calculations ◽  
Portal Of Entry ◽  
Molecular Modeling And Docking ◽  
Materials Studio

In the present study, we will verify the action of hydroxychloroquine-based derivatives on ACE2 which is considered to be the main portal of entry of the SARS-CoV-2 virus and constitutes an exciting target given its relative genetic stability compared to viral proteins. Thus, 81 molecules derived from hydroxychloroquine by substitutions at 4 different positions were generated in-silico and then studied for their affinity for ACE2 by molecular docking. Only 4 molecules were retained because of their affinity and bioavailability demonstrated by molecular dynamics and molecular docking calculations using COSMOtherm and Materials Studio software.

scholarly journals Euryops pectinatus L. Flower Extract Inhibits P-glycoprotein and Reverses Multi-Drug Resistance in Cancer Cells: A Mechanistic Study

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 647 ◽  
Author(s):  
Wafaa M. Elkady ◽  
Iriny M. Ayoub ◽  
Yousra Abdel-Mottaleb ◽  
Mohamed F. ElShafie ◽  
Michael Wink
Keyword(s):  
Molecular Docking ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Inhibitory Activity ◽  
In Silico ◽  
Chemotherapeutic Agents ◽  
Selective Cytotoxicity ◽  
Flower Extract ◽  
P Glycoprotein ◽  
In Silico Molecular Docking

Euryops pectinatus is a South African ornamental plant belonging to family Asteraceae. The present work evaluates the cytotoxic activity and phytochemical profile of the flower extract. Metabolite profiling was performed using HPLC-PDA-ESI-MS/MS. Total phenolics and flavonoids content were assessed. Cytotoxicity was evaluated against 6 different cancer cell lines using MTT assay. The possible underlying mechanism was proposed. We analyzed whether the extract could overcome the resistance of multidrug-resistant cancer cells for doxorubicin. The effect of combination of E. pectinatus with doxorubicin was also studied. Additionally, the potential inhibitory activity of the identified phytochemicals to PB1 protein was analyzed using in silico molecular docking. Twenty-five compounds were tentatively identified. Total phenolic and flavonoid contents represented 49.41 ± 0.66 and 23.37 ± 0.23 µg/mg dried flower extract, respectively. The extract showed selective cytotoxicity against Caco2 cells but its main effect goes beyond mere cytotoxicity. It showed strong inhibition of P-glycoprotein, which helps to overcome multidrug resistance to classical chemotherapeutic agents. In silico molecular docking showed that dicaffeoyl quinic acid, kaempferol-O-rutinoside, rutin, and isorhamnetin-O-rutinoside exhibited the most potent inhibitory activity to PB1 involved in tumor progression. Euryops pectinatus flower heads could have promising selective cytotoxicity alone or in combination with other chemotherapeutic agents to counteract multidrug resistance.

Benzophenone Sulfonamide Derivatives as Interacting Partners and Inhibitors of Human P-glycoprotein

2020 ◽  
Vol 20 (14) ◽  
pp. 1739-1751
Author(s):  
Saira Farman ◽  
Aneela Javed ◽  
Arshia ◽  
Khalid M. Khan ◽  
Abdul Nasir ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Transmembrane Protein ◽  
Homology Model ◽  
Binding Pocket ◽  
Cytotoxicity Assay ◽  
Glycoprotein P ◽  
Diverse Range ◽  
P Glycoprotein ◽  
Ic50 Values ◽  
Nanomolar Range

Background: Human P-glycoprotein (P-gp) is a transmembrane protein that belongs to the ATPBinding Cassette (ABC) transporters family. Physiologically, it exports toxins out of the cell, however, its overexpression leads to the phenomena of Multidrug-Resistance (MDR) by exporting a diverse range of compounds, which are structurally and chemically different from each other, thus creating a hurdle in the treatment of various diseases including cancer. The current study was designed to screen benzophenone sulfonamide derivatives as a class of inhibitors and potential anticancer agents for P-gp. Methods: A total number of 15 compounds were evaluated. These compounds were screened in daunorubicin efflux inhibition assays using CCRF-CEM Vcr1000 cell line that overexpressed human P-gp. Cytotoxicity assay was also performed for active compounds 11, 14, and 13. These scaffolds were then docked in the homology model of human P-gp using mouse P-gp as a template (PDB ID: 4MIM) and the recently published Cryo Electron Microscopy (CEM) structure of human mouse chimeric P-gp to find their interactions with specified residues in the binding pocket. Analysis was performed using Labview VI and Graph pad prism version 5.0. Results: Results revealed the potency of all these compounds in low nanomolar range whereas, compound 14 was found to be most active with IC50 value of 18.35nM±4.90 followed by 11 and 13 having IC50 values of 30.66nM±5.49 and 46.12nM±3.06, respectively. Moreover, IC50 values calculated for 14, 11 and 13 in cytotoxicity assay were found to be 22.97μM±0.026, 583.1μM±0.027 and 117.8μM±0.062, respectively. Docking results showed the interaction of these scaffolds in transmembrane helices (TM) where Tyr307, Tyr310, Tyr953, Met986 and Gln946 were found to be the major interaction partners, thus they might play a significant role in the transport of these scaffolds. Conclusion: Benzophenone sulfonamide derivatives showed IC50 values in low nanomolar range comparable to the standard inhibitor Verapamil, therefore they can be good inhibitors of P-gp and can serve as anticancer agents. Also, they have shown interactions in the transmembrane region sharing the same binding region of verapamil and zosuquidar.

P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil.

1991 ◽  
Vol 9 (1) ◽  
pp. 17-24 ◽  
Author(s):  
T P Miller ◽  
T M Grogan ◽  
W S Dalton ◽  
C M Spier ◽  
R J Scheper ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Continuous Infusion ◽  
Efflux Pump ◽  
Competitive Inhibition ◽  
Transmembrane Protein ◽  
Immunohistochemical Method ◽  
High Dose ◽  
Drug Resistant ◽  
P Glycoprotein ◽  
Clinical Drug

P-glycoprotein is a transmembrane protein thought to function as an efflux pump to detoxify cells. It is associated with multidrug resistance in laboratory systems and has recently been found in human tumors associated with in vitro and clinical drug resistance. We used an immunohistochemical method employing two monoclonal antibodies, JSB-1 and C-219, to detect expression of P-glycoprotein in lymphoma patients. One of 42 newly diagnosed and untreated lymphoma patients (2%) and seven of 11 previously treated and drug-resistant patients (64%) had detectable levels of P-glycoprotein (P less than .001). Based on prior reports suggesting that verapamil sensitizes drug-resistant cancer cells to chemotherapy by competitive inhibition of the P-glycoprotein, we tested the efficacy of verapamil as a chemosensitizer in 18 patients with drug-refractory disease. All patients had previously failed or relapsed within 3 months of a doxorubicin-vincristine-containing drug regimen. Patients received day-1 cyclophosphamide, and 4-day continuous infusion doxorubicin and vincristine and oral dexamethasone (CVAD). CVAD was combined with 5-day continuous infusion verapamil given at maximally tolerated dose. Overall, 13 of 18 patients (72%) responded to treatment including five complete remissions (CRs; 28%). The median duration of response was 200 days and median survival was 242 days. The dose-limiting toxicity of the verapamil infusion was temporary cardiac dysfunction including hypotension, congestive heart failure, and cardiac arrhythmia. We conclude that the P-glycoprotein is uncommonly expressed in untreated lymphomas and frequently expressed in clinically drug-resistant disease, and that chemotherapy using CVAD plus maximally tolerated doses of verapamil results in a high response rate in patients carefully selected for clinical drug resistance.

scholarly journals N-(5-Morpholino-2-arylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)carboxamides as Potential Fer/FerT Kinase Inhibitors. Homology Modeling, Molecular Docking Studies and In Silico ADMET Profiling

2021 ◽  
Vol 11 (6) ◽  
pp. 14413-14432
Keyword(s):  
Molecular Docking ◽  
Comparative Analysis ◽  
Homology Modeling ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Docking Studies ◽  
Experimental Conditions ◽  
Reference Drug ◽  
Modeling Methods ◽  
In Silico Admet

This study has comparatively evaluated the degree of affinity of N-(5-morpholino-2-arylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)carboxamides 2a-f and 6-(4-isopropylphenyl)-2-(4-((4-methylpiperazin-1-yl)methyl)piperidin-1-yl)imidazo[2,1-b][1,3,4]thiadiazole (E260) to Fer kinase using molecular modeling methods. The Fer kinase model has been generated by homology modeling. It has been shown that compounds 2a-f predominantly form stronger complexes with this enzyme than the reference drug E260. In silico ADMET prediction of the properties of compounds 2a-f and E260 has been carried out. Comparative analysis of the obtained results has shown that compounds 2a-f are not inferior to the reference drug - E260 and even surpass it in most parameters. All examined compounds 2a-f have shown good results under in silico experimental conditions and can be recommended for further study on tumor cell cultures.

scholarly journals CONSTRUÇÃO, OTIMIZAÇÃO E ANCORAGEM MOLECULAR DE SUBSTÂNCIAS BIOATIVAS EM BIOMACROMOLÉCULAS: UM TUTORIAL PRÁTICO

Química Nova ◽  
2021 ◽  
Author(s):  
Victor Batista ◽  
Renan Farias ◽  
Leonardo Simões ◽  
Nailton Nascimento-Júnior
Keyword(s):  
Molecular Docking ◽  
Small Molecules ◽  
In Silico ◽  
Low Cost ◽  
Research Groups ◽  
Efficient Tool ◽  
Bioactive Substances ◽  
Funding Agencies ◽  
Docking Calculations ◽  
Construction Optimization

CONSTRUCTION, OPTIMIZATION AND MOLECULAR DOCKING OF BIOACTIVE SUBSTANCES IN BIOMACROMOLECULES: A PRACTICAL TUTORIAL. In the last two decades, increasing advances in molecular biology and instrumental analysis for solving macromolecular structures have amplified the applicability of cheminformatics in drug discovery. In particular, molecular docking, an in silico structural-based method, has prospered as an efficient tool for understanding molecular interactions that drives formation of stable receptor-ligand systems. Brazil affords many research groups working hard on this subject; however, there is a lack of material in the Portuguese language, teaching how to apply molecular docking methodologies. Herein, we define and discuss a simple and low-cost workflow for molecular docking evaluation, comprising software installation (supplemental material) and how to use them for construction of small-molecules, perform docking calculations, analysis of the results and the preparation of quality figures. Given that, we have used free software and web-servers, as well as in silico tools supported by national funding agencies.

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