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Updated: Oct 22, 2026

Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
08:49

Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis

Published on: June 20, 2025

Assessment of the bioactive conformation of the farnesyltransferase protein binding recognition motif by

F J Corcho1, M Filizola, J J Perez

  • 1Dept. d'Enginyeria Quimica, UPC, ETS d'Enginyers Industrials de Barcelona, Spain.

Journal of Biomolecular Structure & Dynamics
|May 20, 1999
PubMed

Insights

Computational analysis revealed the bioactive conformation of a peptide inhibitor for Ras farnesyltransferase. This minimum peptide sequence is crucial for targeting farnesyltransferase in cancer therapy research.

Area of Science:

  • Biochemistry
  • Computational Chemistry
  • Molecular Biology

Background:

  • Ras farnesyltransferase (FTase) is a key enzyme in signal transduction.
  • FTase inhibition shows promise for cancer therapy by suppressing Ras-transformed phenotypes and inducing tumor regression.

Purpose of the Study:

  • To computationally determine the bioactive conformation of the minimum peptide inhibitor of FTase: Cys-Val-Phe-Met.
  • To analyze the conformational preferences of active and inactive FTase inhibitor analogs.

Main Methods:

  • Conformational space searches using simulated annealing protocols.
  • Analysis of four peptide analogs: two active and two inactive inhibitors.
  • Classification of low-energy conformations and cross-comparison of structural motifs.

Main Results:

  • Identified key structural motifs characterizing the bioactive conformation.
  • The bioactive conformation features a C14 pseudo-ring (Cys1-Met4 hydrogen bond) and a C11 pseudo-ring (Cys1-Tic3).
  • The Cys1 thiol group in the bioactive conformation is oriented towards the Met4 carboxylate.

Conclusions:

  • The study elucidates the specific structural requirements for FTase inhibition by minimal peptide sequences.
  • Understanding the bioactive conformation provides insights for designing novel FTase inhibitors for cancer treatment.

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