Rational design and preliminary validation of novel 6-phosphogluconate dehydrogenase (6PGD) inhibitors using parietin as a lead

Abstract

Parietin has documented anti-tumour properties through inhibition of the 6-phosphogluconate dehydrogenase (6PGD) enzyme which is involved in tumour cell metabolism as part of the overactive pentose phosphate pathway (PPP). In this study, the parietin molecule was used as a scaffold for the design and identification of new molecules capable of similar modulation of the 6PGD enzyme using both virtual screening and de novo design. The study was guided by crystallographic deposition 2IZ1 which describes small molecule inhibitor PEX bound to 6PGD. PEX was extracted from 2IZ1 and the parietin structure was modelled in SYBYL®-X. Using the parietin structure as a general pharmacophore, 4 hit molecules were identified using virtual screening from the online ZINC Pharmer database®. The next phase of the study involved the identification of the optimal conformer of parietin inside the 6PGD ligand binding pocket. The optimal conformer identified through this study was used as the basis for the de novo approach. A 2D topology map describing the interactions of the optimal conformer of parietin with the 6PGD ligand binding pocket was generated, and 3 seed molecules were subsequently modelled keeping the moieties essential for binding. These seed structures were inputted in LigBuilder v1.2 where the molecules were allowed to grow within the crystallographically described 6PGD ligand binding pocket. A series of molecules was consequently generated. The highest affinity Lipinski Rule compliant structure was compared with its lowest affinity counterparts from an atomic perspective based on the creation of 2D topology maps which described their critical interactions with the target receptor. A similar comparison was also carried out between the highest affinity de novo designed molecules and the lead molecule parietin. This allowed identification of the conserved amino acids critical to 6PGD modulation. These include the amino acids Ala12, Arg34 , Asn33 and Val74.