Journal of Molecular Modeling

, Volume 18, Issue 11, pp 4843–4863 | Cite as

Application of docking-based comparative intermolecular contacts analysis to validate Hsp90α docking studies and subsequent in silico screening for inhibitors

  • Mahmoud A. Al-Sha’er
  • Mutasem O. TahaEmail author
Original Paper


Heat shock protein (Hsp90α) has been recently implicated in cancer, prompting several attempts to discover and optimize new Hsp90α inhibitors. Towards this end, we docked 83 diverse Hsp90α inhibitors into the ATP-binding site of this chaperone using several docking–scoring settings. Subsequently, we applied our newly developed computational tool—docking-based comparative intramolecular contacts analysis (dbCICA)—to assess the different docking conditions and select the best settings. dbCICA is based on the number and quality of contacts between docked ligands and amino acid residues within the binding pocket. It assesses a particular docking configuration based on its ability to align a set of ligands within a corresponding binding pocket in such a way that potent ligands come into contact with binding site spots distinct from those approached by low-affinity ligands, and vice versa. The optimal dbCICA models were translated into valid pharmacophore models that were used as 3D search queries to mine the National Cancer Institute’s structural database for new inhibitors of Hsp90α that could potentially be used as anticancer agents. The process culminated in 15 micromolar Hsp90α ATPase inhibitors.


Validating docking settings and Building pharmacophore models against Hsp90 based on successful dbCICA models


Docking LigandFit dbCICA Heat shock protein 90α Anticancer 

Supplementary material

894_2012_1479_MOESM1_ESM.doc (7.4 mb)
ESM 1 (DOC 7628 kb)


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Faculty of PharmacyZarqa UniversityZarqaJordan
  2. 2.Drug Discovery Unit, Department of Pharmaceutical Sciences, Faculty of PharmacyUniversity of JordanAmmanJordan

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