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Comput Biol Chem. 2018 Jun;74:63-75. doi: 10.1016/j.compbiolchem.2018.02.014. Epub 2018 Feb 24.

Elucidation of chemosensitization effect of acridones in cancer cell lines: Combined pharmacophore modeling, 3D QSAR, and molecular dynamics studies.

Author information

1
Centre for Molecular Cancer Research (CMCR), Vishnu Institute of Pharmaceutical Education and Research, Narsapur, India.
2
Clinical Research Department, Emcure Pharmaceuticals Ltd., Pune, India.
3
Department of Pharmaceutical Chemistry, Sultan Ul Uloom College of Pharmacy, Hyderabad, India.
4
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
5
Department of Pharmaceutical Chemistry, Gland Institute of Pharmaceutical Sciences, Narsapur, India.
6
Centre for Molecular Cancer Research (CMCR), Vishnu Institute of Pharmaceutical Education and Research, Narsapur, India; Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: rajendraprasad.vvs@viper.ac.in.

Abstract

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 r2cv 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.

KEYWORDS:

3D QSAR; Acridones; Molecular dynamics; Multidrug resistance; Pharmacophore modeling; p-Glycoprotein inhibition

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