Journal of Computer-Aided Molecular Design

, Volume 27, Issue 4, pp 347–363 | Cite as

In silico model for P-glycoprotein substrate prediction: insights from molecular dynamics and in vitro studies

  • Rameshwar Prajapati
  • Udghosh Singh
  • Abhijeet Patil
  • Kailas S. Khomane
  • Pravin Bagul
  • Arvind K. Bansal
  • Abhay T. SangamwarEmail author


P-glycoprotein (P-gp) is a plasma membrane efflux transporter belonging to ATP-binding cassette superfamily, responsible for multidrug resistance in tumor cells. Over-expression of P-gp in cancer cells limits the efficacy of many anticancer drugs. A clear understanding of P-gp substrate binding will be advantageous in early drug discovery process. However, substrate poly-specificity of P-gp is a limiting factor in rational drug design. In this investigation, we report a dynamic trans-membrane model of P-gp that accurately identified the substrate binding residues of known anticancer agents. The study included homology modeling of human P-gp based on the crystal structure of C. elegans P-gp, molecular docking, molecular dynamics analyses and binding free energy calculations. The model was further utilized to speculate substrate propensity of in-house anticancer compounds. The model demonstrated promising results with one anticancer compound (NSC745689). As per our observations, the molecule could be a potential lead for anticancer agents devoid of P-gp mediated multiple drug resistance. The in silico results were further validated experimentally using Caco-2 cell lines studies, where NSC745689 exhibited poor permeability (P app 1.03 ± 0.16 × 10−6 cm/s) and low efflux ratio of 0.26.


P-glycoprotein Substrate binding Molecular dynamics Molecular modeling MDR Caco-2 

Supplementary material

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Supplementary material 1 (DOCX 30091 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Rameshwar Prajapati
    • 1
  • Udghosh Singh
    • 1
  • Abhijeet Patil
    • 1
  • Kailas S. Khomane
    • 2
  • Pravin Bagul
    • 2
  • Arvind K. Bansal
    • 2
  • Abhay T. Sangamwar
    • 1
    Email author
  1. 1.Department of PharmacoinformaticsNational Institute of Pharmaceutical Education and Research (NIPER)S.A.S. NagarIndia
  2. 2.Department of PharmaceuticsNational Institute of Pharmaceutical Education and Research (NIPER)S.A.S. NagarIndia

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