Title

Virtual screening and pharmacophore studies for ftase inhibitors using Indian plant anticancer compounds database

Authors

Abdul Hafeez Khan, Alok Prakash, Dinesh Kumar, Anil Kumar Rawat, Rajeev Srivastava, Shipra Srivastava**

Affiliation

Biotechnology and Bioinformatics Division, BIOBRAINZ, 566/29 J, Jai Prakash Nagar, Alambagh, Lucknow 226005, U.P., India

E-mail*

shipra.srivastava09@gmail.com; * Corresponding author

Phone

91- 05224042284

Article Type

Hypothesis

Date

received  March 4, 2010; revised April 29, 2010; accepted  June 8, 2010; published online July 6, 2010

Farnesyl transferase (FTase) is an enzyme responsible for post-translational modification in proteins having a carboxy-terminal CaaX motif in human. It catalyzes the attachment of a lipid group in proteins of RAS superfamily, which is essential in signal transduction. FTase has been recognized as an important target for anti cancer therapeutics. In this work, we performed virtual screening against FTase with entire 125 compounds from Indian Plant Anticancer Database using AutoDock 3.0.5 software. All compounds were docked within binding pocket containing Lys164, Tyr300, His248 and Tyr361 residues in crystal structure of FTase. These complexes were ranked according to their docking score, using methodology that was shown to achieve maximum accuracy. Finally we got three potent compounds with the best Autodock docking Score (Vinorelbine: -21.28 Kcal/mol, Vincristine: -21.74 Kcal/mol and Vinblastine: -22.14 Kcal/mol) and their energy scores were better than the FTase bound co-crystallized ligand (L- 739: –7.9 kcal/mol). These three compounds belong to Vinca alkaloids were analyzed through Python Molecular Viewer for their interaction studies. It predicted similar orientation and binding modes for these compounds with L-739 in FTase.Thus from the complex scoring and binding ability it is concluded that these Vinca alkaloids could be promising inhibitors for FTase. A 2-D pharmacophore was generated for these alkaloids using LigandScout to confirm it. A shared feature pharmacophore was also constructed that shows four common features (one hydogen bond Donar, Two hydrogen bond Acceptor and one ionizable area) help compounds to interact with this enzyme. 

Keywords

Virtual Screening, Indian Plant Anticancer Compounds Database, Signal Transduction, Autodock, LigandScou.

Citation

Hafeez khan et al. Bioinformation 5(2): 62-66 (2010)

Edited by

P. Kangueane

ISSN

0973-2063

Publisher

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.