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

Vishal Pandya 
PhD Student
Department of Biochemistry


Date: September 26, 2022
Time: 1:00 p.m. to 2:00 p.m. 
Room: CSF 1302

Human farnesyl pyrophosphate synthase (FPPS) is a key regulatory enzyme of the isoprenoid synthetic pathway. As a direct controller of intracellular levels of farnesyl pyrophosphate (FPP), the enzyme is a well-established drug target. For example, the downregulation of small GTPase prenylation is one of the known mechanisms of action for the anticancer effects of FPPS inhibition. Continued drug discovery efforts identified allosteric inhibitors of FPPS that inhibit the enzyme by preventing its closing, a conformational change required for its catalytic action. 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. The opening of the new pocket is observed only in the presence of a ligand that binds to the pocket and occurs through a conformational change that simultaneously closes the allosteric pocket. In the present study, we explore the possibility of pharmacologically targeting the newly found cryptic pocket of FPPS. 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 conformation. 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 soon be examined in an in vitro inhibition assay. The binding of confirmed inhibitors will be characterized by X-ray crystallography.