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Structural Chemistry

, Volume 30, Issue 1, pp 213–226 | Cite as

Computational fragment-based design of Wee1 kinase inhibitors with tricyclic core scaffolds

  • Maaged Abdullah
  • Lalitha GuruprasadEmail author
Original Research
  • 187 Downloads

Abstract

Wee1 is cell cycle protein comprising a kinase domain and is a validated cancer target. We have designed molecules with variable tricyclic core scaffolds [6-6-5] system and extended them based on the chemical space available in the active site of Wee1 kinase using de novo drug design. The core scaffolds and linking fragments were extracted from pharmacophore-based virtual screening of ZINC and PubChem databases and Ludi library. These molecules bind the hinge region of kinase active site and form hydrogen bonds as confirmed from molecular docking, molecular dynamics simulations, and MM_PBSA calculations. When compared with reference inhibitors, AZD1775 and PHA-848125, the de novo designed molecules also show good docking scores and stability, retained non-covalent interactions, and high binding free energies contributed from active site residues.

Keywords

Wee1 kinase Tricyclic system Scaffolds Fragments De novo design ADME Molecular docking Front and back pockets MD simulations Binding free energy 

Notes

Acknowledgements

The authors thank CMSD, University of Hyderabad for providing computational facilities. MA thanks Ministry of Higher Education & Scientific Research—Republic of Yemen.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This chapter does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

11224_2018_1176_MOESM1_ESM.docx (15 kb)
ESM 1 (DOCX 14 kb)

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Authors and Affiliations

  1. 1.School of ChemistryUniversity of HyderabadHyderabadIndia

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