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Journal of Molecular Modeling

, Volume 14, Issue 10, pp 911–921 | Cite as

Pharmacophore mapping of a series of pyrrolopyrimidines, indolopyrimidines and their congeners as multidrug-resistance-associated protein (MRP1) modulators

  • Nilesh R. Tawari
  • Seema Bag
  • Mariam S. DeganiEmail author
Original Paper

Abstract

Pharmacophore mapping studies were undertaken for a series of molecules belonging to pyrrolopyrimidines, indolopyrimidines and their congeners as multidrug resistance-associated protein (MRP1) modulators. A five-point pharmacophore with two hydrogen bond acceptors (A), one lipophilic/hydrophobic group (H), one positive ionic feature (P) and one aromatic ring (R) as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of r 2 = 0.799 for training set molecules. The model generated showed excellent predictive power, with a correlation coefficient Q 2 = 0.679 for an external test set of 20 molecules. The pharmacophore was further validated using four structurally diverse compounds with MRP1 modulatory activity. These compounds mapped well onto four of the five features of the pharmacophore. The pharmacophore proposed here was then utilised for the successful retrieval of active molecules with diverse chemotypes from database search. The geometry and features of pharmacophore are expected to be useful for the design of selective MRP1 inhibitors.

Figure

Alignment of multidrug resistance-associated protein (MRP1) inhibitors with the developed pharmacophore.

Keywords

Multidrug resistance-associated protein1 Multidrug resistance Pharmacophore mapping 3D-QSAR 

Notes

Acknowledgements

Nilesh R. Tawari is thankful to the Department of Biotechnology (DBT), India and Seema Bag is thankful to the University Grand Commission (UGC), India, for financial support.

Supplementary material

894_2008_330_MOESM1_ESM.doc (110 kb)
ESM 1. Tables of the actual vs predicted activities for training and test set are available as supplementary material. (DOC 109 KB)

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Nilesh R. Tawari
    • 1
  • Seema Bag
    • 1
  • Mariam S. Degani
    • 1
    Email author
  1. 1.Department of Pharmaceutical Sciences and Technology, Institute of Chemical TechnologyUniversity of MumbaiMumbaiIndia

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