Elucidation of chemosensitization effect of acridones in cancer cell lines: Combined pharmacophore modeling, 3D QSAR, and molecular dynamics studies
| Autor: | B. S. Sastry, Godefridus J. Peters, Deepak Reddy Gade, V.V.S. Rajendra Prasad, Rajesh Babu Yarlagadda, Amareswararao Makkapati |
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| Přispěvatelé: | Medical oncology laboratory, AGEM - Digestive immunity, CCA - Cancer biology and immunology, VU University medical center |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Quantitative structure–activity relationship Stereochemistry In silico Quantitative Structure-Activity Relationship Antineoplastic Agents Ligands Biochemistry 03 medical and health sciences chemistry.chemical_compound Molecular dynamics 0302 clinical medicine Structural Biology Chemosensitization Molecule Humans Homology modeling Cell Proliferation Molecular Structure Organic Chemistry Acridone Computational Mathematics 030104 developmental biology chemistry 030220 oncology & carcinogenesis MCF-7 Cells Pharmacophore Drug Screening Assays Antitumor Acridones |
| Zdroj: | Computational Biology and Chemistry, 74, 63-75. Elsevier Ltd Gade, D R, Makkapati, A, Yarlagadda, R B, Peters, G J, Sastry, B S & Rajendra Prasad, V V S 2018, ' Elucidation of chemosensitization effect of acridones in cancer cell lines: Combined pharmacophore modeling, 3D QSAR, and molecular dynamics studies ', Computational Biology and Chemistry, vol. 74, pp. 63-75 . https://doi.org/10.1016/j.compbiolchem.2018.02.014 |
| ISSN: | 1476-9271 |
| DOI: | 10.1016/j.compbiolchem.2018.02.014 |
| Popis: | Overexpression of P-glycoprotein (P-gp) leads to the emergence of multidrug resistance (MDR) in cancer treatment. Acridones have the potential to reverse MDR and sensitize cells. In the present study, we aimed to elucidate the chemosensitization potential of acridones by employing various molecular modelling techniques. Pharmacophore modeling was performed for the dataset of chemosensitizing acridones earlier proved for cytotoxic activity against MCF7 breast cancer cell line. Gaussian-based QSAR studies also performed to predict the favored and disfavored region of the acridone molecules. Molecular dynamics simulations were performed for compound 10 and human P-glycoprotein (obtained from Homology modeling). An efficient pharmacophore containing 2 hydrogen bond acceptors and 3 aromatic rings (AARRR.14) was identified. NCI 2012 chemical database was screened against AARRR.14 CPH and identified 25 best-fit molecules. Potential regions of the compound were identified through Field (Gaussian) based QSAR. Regression analysis of atom-based QSAR resulted in r2 of 0.95 and q2 of 0.72, whereas, regression analysis of field-based QSAR resulted in r2 of 0.92 and q2 of 0.87 along with r2 cv as 0.71. The fate of the acridone molecule (compound 10) in the P-glycoprotein environment is analyzed through analyzing the conformational changes occurring during the molecular dynamics simulations. Combined data of different in silico techniques provided basis for deeper understanding of structural and mechanistic insights of interaction phenomenon of acridones with P-glycoprotein and also as strategic basis for designing more potent molecules for anti-cancer and multidrug resistance reversal activities. |
| Databáze: | OpenAIRE |
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