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

Abstract

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

Figure 1

A detailed flowchart summarizing the methodology implemented is shown.

Figure 2

2-D Pharmacophore model of alkaloid compound (a) Vinorelbine, (b) Vincristine, (c) Vinblastine generated by LigandScout.

Figure 3

Shared Feature Pharmacophore of Vinorelbine, Vincristine and Vinblastine showing four common features (one hydrogen bond Donar: green sphere, two hydrogen bonds Acceptor: Red sphere and one ionizable area: Blue asterisk).