Farnesyltransferase and geranylgeranyltransferase I: structures, mechanism, inhibitors and molecular modeling

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Farnesyltransferase (FTase) and geranylgeranyltransferase type I (GGTase-I) are enzymes involved in essential post-translational modifications of Ras proteins.
• These modifications are critical for Ras protein function and are implicated in various cancers and diseases.

Purpose of the Study:

• To provide a comprehensive overview of FTase and GGTase-I, including their structures and biological functions.
• To summarize current inhibitors and highlight drug candidates in clinical trials targeting these enzymes.
• To survey recent advances in computer-aided drug design (CADD) and molecular modeling for FTase and GGTase-I.

Main Methods:

• Literature review of scientific publications on FTase and GGTase-I.
• Analysis of structural and functional data of the enzymes.
• Summary of preclinical and clinical data for inhibitors.
• Review of CADD and molecular modeling studies.

Main Results:

• FTase and GGTase-I play vital roles in prenylation, a process crucial for Ras signaling.
• Numerous inhibitors targeting FTase and GGTase-I have been developed, with several progressing to clinical trials.
• CADD and molecular modeling have significantly contributed to understanding enzyme mechanisms and designing novel inhibitors.

Conclusions:

• FTase and GGTase-I represent promising therapeutic targets for Ras-induced cancers and other diseases.
• The development of specific inhibitors and the application of CADD are advancing the therapeutic potential of targeting these enzymes.
• Further research into enzyme structures, functions, and inhibitor design holds promise for novel treatments.