Identification of potential inhibitors of kidney glutaminase using molecular docking simulations

Kidney-type mitochondrial glutaminase (GLS) is a phosphate-activated amidohydrolaseprimarily active in the brain and kidney. It plays a crucial role in energy generation, neurotransmitterproduction, and kidney acid-base balance by breaking down glutamine. Alternative splicing generatesmultiple transcript variants. Targeting this protein may hold promise for suppressing and treating cancer,given its involvement in metabolic diseases. [۱]. As a result, we have sought to explore the potential ofinhibiting this protein as a new avenue for controlling metabolic diseases. Previous studies have shownthat the molecule (PubChem ID:۷۱۵۷۷۴۲۶) was able to inhibit GLS [۲]. Using this molecule as atemplate, a molecular library from SWISS-SIMILARITY database were created and a set of ۵۷molecules were identified. Subsequently, PyRex software were used in an in-silico environment toconduct docking simulations of GLS with the molecules in the library [۳]. The resulting data revealedthat among this library, three molecules (CIDs: ۳۶۷۵۱۷۶, ۳۶۷۹۹۹۱, ۳۶۸۰۰۰۳) interacted with GLS witha minimum ΔG less than -۱۲.۱. In addition interacting residues were identified using Discovery studiosoftware as follows: molecule (۳۶۸۰۰۰۳) with residues chain C: GLU۱۷۰, ASN۱۸۲, HIS۱۸۸, LEU۱۷۹,LYS۱۷۸, PHE۱۸۰, LEU۱۸۱, PHE۱۷۶,chain D: LEU۱۷۲, ARG۱۷۳, chain B:LYS۱۸۴, PHE۱۸۶,TYR۲۵۸, , molecule (۳۶۷۵۱۷۶) with residues chain B: LEU۱۸۷,HIS۱۹۴, LEU۱۸۵, LYS۱۸۴, TYR۲۵۸,ASN۱۸۸, GLU۱۸۹, chain C: ARG۱۷۵, LYS۱۷۸, TYR۲۵۲, PHE۱۸۰, LEU۱۸۱, ASN۱۸۲, GLU۱۸۳,LEU۱۷۹, PHE۱۷۶, chain D: ARG۱۷۳, and molecule (۳۶۷۹۹۹۱) with residues chain C: HIS۱۸۸,LEU۱۸۱, PHE۱۷۶, LEU۱۷۹, TYR۲۵۲, ARG۱۷۵, ASN۱۸۲, GLU۱۸۳, chain B: TYR۲۵۸, ASN۱۸۸,LEU۱۸۵, LYS۱۸۴, chain D: ARG۱۷۳. In conclusion, it seems that these molecules will be able to inhibitGLS and potentially control metabolic diseases, especially cancer. For the future studies, it isrecommended that the toxicity and efficacy of these potential inhibitors be evaluated in vitro and invivo.

کلیدواژه ها:

Glutaminase ، Pyrex ، GLS inhibitor ، docking