Towards the discovery of cryptic pocket inhibitors of farnesyl pyrophosphate synthase as novel anticancer drug candidates

Vishal Pandya
PhD Student
Department of Biochemistry

Date: February 12, 2024
Time: 1:00 p.m. to 2:00 p.m. 
Room: CSF 1302

Abstract:

Farnesyl pyrophosphate synthase (FPPS) in humans functions as a central regulatory enzyme in the isoprenoid synthetic pathway. As a direct modulator of intracellular farnesyl pyrophosphate (FPP) levels, this enzyme is recognized as a promising target for drug discovery. Notably, FPPS inhibition is associated with anticancer effects, with one established mechanism involving the downregulation of small GTPase prenylation. Continued drug discovery efforts have identified allosteric inhibitors of FPPS, which inhibit the enzyme by preventing its closing, a conformational change necessary for its catalytic activity. However, the presence of charged functional groups in these inhibitors makes them poor drug candidates. Recently, we have discovered a previously unidentified binding pocket in FPPS that appears to be better druggable than its allosteric pocket. This pocket is only observed in the presence of a bound ligand, and its opening requires a conformational change that simultaneously closes the allosteric pocket. In the present study, we explore the possibility of targeting the newly found cryptic pocket for FPPS inhibition. Our research objective is two-fold: i) to understand the molecular mechanism underpinning the ligand-induced cryptic pocket formation and ii) to identify high-affinity cryptic pocket ligands as new FPPS inhibitors. To this end, we first carried out several sets of extended molecular dynamics (MD) simulations of FPPS. Our results indicate that once formed, the cryptic pocket does not spontaneously collapse to its closed state, even in the absence of a bound ligand. The simulation data also suggest that the residues Phe239 and Ile348 play an important role in maintaining the pocket in its open state. Subsequent screening of small molecule libraries by molecular docking has identified potential cryptic pocket ligands with predicted binding affinity greater than that of the current ligands. The inhibitory potency of the candidate compounds will be examined in an in vitro inhibition assay. The binding of confirmed inhibitors will be characterized by differential scanning fluorimetry and X-ray crystallography.