Modeling Study of Phenylsulfonylfuroxan Derivatives as P-gp Inhibitors: A Combined Approach of CoMFA, CoMSIA and HQSAR

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 14, 10 Issues, 2014


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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  • 26th of 59 in Chemistry, Medicinal
  • 99th of 197 in Oncology

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Editor-in-Chief:
Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France


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Modeling Study of Phenylsulfonylfuroxan Derivatives as P-gp Inhibitors: A Combined Approach of CoMFA, CoMSIA and HQSAR

Author(s): Changdev G. Gadhe, Anand Balupuri, Pavithra K. Balasubramanian and Seung Joo Cho

Affiliation: College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu Gwangju 501-759, Republic of Korea

Abstract

Multidrug resistance (MDR) is a phenomenon whereby cancer cells experience intrinsic or acquired resistance to a broad spectrum of structurally and functionally distinct chemotherapeutic agents. Permeability glycoprotein (P-gp) is the key protein responsible for the development of MDR in cancer cells, as it exports chemotherapeutic agents from cells. In the present study, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram quantitative structure activity relationship (HQSAR) techniques were used to derive predictive models for phenylsulfonylfuroxan derivatives as P-gp inhibitors. Cross-validated correlation coefficients (q2) of 0.811, 0.855, and 0.907 and non-cross-validated correlation coefficients (r2) of 0.87, 0.985, and 0.973 were obtained for CoMFA, CoMSIA, and HQSAR derived models, respectively. The predictive power of the models were assessed using an external test set of five compounds and showed reasonable external predictabilities (r2pred) of 0.704, 0.517, and 0.713, respectively. Contour and atomic contribution maps were generated to investigate physicochemical requirements of ligands for better receptor binding affinity. 3D Contour maps suggested molecular interactions such as steric and electrostatic effects and hydrogen bond formation. However, atomic contribution maps indicated that ortho and para positions of the R1 phenylsulfonyl ring are the most desirable regions to modulate P-gp antagonism. The 3rd and 4th positions of the central five-membered ring were also found to be important. Our results are in line with previous reports. Information obtained from the contour and atomic contribution maps were utilized to design more potent compounds containing different R1 fragments. In addition, the activities of these more potent compounds were predicted using derived models

Keywords: Anti-cancer agent, CoMFA, CoMSIA, HQSAR, P-gp, Phenylsulfonylfuroxan

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Article Details

Volume: 13
First Page: 1
Last Page: 13
Page Count: 13
DOI: 10.2174/18715206113136660335
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