Rational design and preliminary validation of novel glutaminase C modulators

Abstract

Glutaminolysis is a process which drives cell proliferation in tumours. This process is driven by Glutaminase C (Gc). Literature indicates that Gc is over-expressed in solid tumours mainly those of the lung and that its antagonism could inhibit tumour growth. The objective in this study is to design & identify novel Gc modulators through Virtual Screening (VS) & de novo design. The design of this project uses high affinity Gc inhibitor experimental molecule CB-839, used as a lead for the identification of optimised analogues using VS. A consensus pharmacophore was generated by superimposing pharmacophores of inhibitor molecules obtained from PDB crystallographic depositions 5HL1 & 5WJ6 using Ligand Scout®. Sybyl-X® was used to model a protomol; followed by docking of hits obtained through VS. The ligand binding affinities of the 2 hit molecular structures were calculated in Sybyl-X®. The de novo approach was used to design novel modulators, where seed structures derived from CB-839 were modelled and allowed growth within the CB-839 ligand binding pocket (LBP). The main outcome of this project is to obtain two molecular cohorts of high affinity lead-like Gc modulators. Through virtual screening, 2 high affinity lead-like molecules were yielded; which are structurally diverse from the lead. CB-839 derived seeds were modelled and will be docked into the Gc LBP in de novo phase. This study was valuable in modelling a unique pharmacophore that explored maximal pharmacophoric space using VS. The de novo design was used as a complementary approach. The optimal structures will be optimised further.