scholarly journals In silico structure-based screening of versatile P-glycoprotein inhibitors using polynomial empirical scoring functions

2014 ◽  
pp. 1 ◽  
Author(s):  
Sergey Shityakov ◽  
Carola Foerster
Keyword(s):  
In Silico ◽  
Scoring Functions ◽  
P Glycoprotein ◽  
Glycoprotein Inhibitors

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.

Status of Flavonols as P-Glycoprotein Inhibitors in Cancer Chemotherapy

2009 ◽  
Vol 5 (2) ◽  
pp. 89-99 ◽  
Author(s):  
Tripta Bansal ◽  
Manu Jaggi ◽  
Roop Khar ◽  
Sushama Talegaonkar
Keyword(s):  
Cancer Chemotherapy ◽  
P Glycoprotein ◽  
Glycoprotein Inhibitors

scholarly journals Identification of New Potential Inhibitors of Quorum Sensing through a Specialized Multi-Level Computational Approach

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2600
Author(s):  
Fábio G. Martins ◽  
André Melo ◽  
Sérgio F. Sousa
Keyword(s):  
Virtual Screening ◽  
Quorum Sensing ◽  
In Silico ◽  
Bacterial Infections ◽  
Extracellular Polymeric Substances ◽  
Free Energy Calculations ◽  
Ligand Docking ◽  
Screening Tests ◽  
Scoring Functions ◽  
Potential Inhibitors

Biofilms are aggregates of microorganisms anchored to a surface and embedded in a self-produced matrix of extracellular polymeric substances and have been associated with 80% of all bacterial infections in humans. Because bacteria in biofilms are less amenable to antibiotic treatment, biofilms have been associated with developing antibiotic resistance, a problem that urges developing new therapeutic options and approaches. Interfering with quorum-sensing (QS), an important process of cell-to-cell communication by bacteria in biofilms is a promising strategy to inhibit biofilm formation and development. Here we describe and apply an in silico computational protocol for identifying novel potential inhibitors of quorum-sensing, using CviR—the quorum-sensing receptor from Chromobacterium violaceum—as a model target. This in silico approach combines protein-ligand docking (with 7 different docking programs/scoring functions), receptor-based virtual screening, molecular dynamic simulations, and free energy calculations. Particular emphasis was dedicated to optimizing the discrimination ability between active/inactive molecules in virtual screening tests using a target-specific training set. Overall, the optimized protocol was used to evaluate 66,461 molecules, including those on the ZINC/FDA-Approved database and to the Mu.Ta.Lig Virtual Chemotheca. Multiple promising compounds were identified, yielding good prospects for future experimental validation and for drug repurposing towards QS inhibition.

Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites

2013 ◽  
Vol 134 (2) ◽  
pp. 235-243 ◽  
Author(s):  
Laura M. Alcantara ◽  
Junwon Kim ◽  
Carolina B. Moraes ◽  
Caio H. Franco ◽  
Kathrin D. Franzoi ◽  
...  
Keyword(s):  
Malaria Parasites ◽  
P Glycoprotein ◽  
Glycoprotein Inhibitors

NEW 4-ARYL-1,4-DIHYDROPYRIDINES AND 4-ARYLPYRIDINES AS P-GLYCOPROTEIN INHIBITORS

2004 ◽  
Vol 33 (3) ◽  
pp. 321-328 ◽  
Author(s):  
Xiao-fei Zhou ◽  
Linping Zhang ◽  
Elaine Tseng ◽  
Elizabeth Scott-Ramsay ◽  
Jerome J. Schentag ◽  
...  
Keyword(s):  
P Glycoprotein ◽  
Glycoprotein Inhibitors

Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors

2021 ◽  
Vol 64 (19) ◽  
pp. 14895-14911
Author(s):  
Shuo Yuan ◽  
Bo Wang ◽  
Qing-Qing Dai ◽  
Xiao-Nan Zhang ◽  
Jing-Ya Zhang ◽  
...  
Keyword(s):  
P Glycoprotein ◽  
Quinazoline Derivatives ◽  
Orally Bioavailable ◽  
Glycoprotein Inhibitors
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