Drug repositioning as an approach to search for potential pharmacological chaperones of human glucocerebrosidase

Mutations in the glucocerebrosidase (GBA) gene are the most common risk factor for developing Parkinson’s disease (PD). In the homozygous, as well as in the compound heterozygous state, mutations in this gene lead to a decrease in the enzymatic activity of glucocerebrosidase (GC), an increase in the level of its substrate hexosylsphingosine (HexSph) both in brain cells and peripheral blood, and the development of a hereditary disease belonging to the class lysosomal storage disease Gaucher disease (GD). The literature is increasingly discussing the use of GC pharmacological chaperones (PC) for the treatment of both GBA-PD and neuropathic forms of GD. The aim of the study was to identify among a wide range of known drugs potential PC of the most common mutant form of N370S GC, which are not competitive inhibitors of the enzyme.

The studies were carried out by molecular modeling methods in two stages, using the atomic model of the N370S GC mutant form that we constructed earlier. First, a virtual screening of 2089 chemical compounds approved for use in clinical practice was carried out, asaresult of which 26 compounds were selected that have the smallest value of the calculated evaluation function characterizing protein affinity. These drugs belonged to different pharmacological groups, of which 6 were selected for further study, which can be taken in clinical practice for a long time. The stability of six complexes of GC with selected chemical compounds was checked by the method of molecular dynamics with explicit allowance for the aqueous environment. The free energy of binding of four compounds (flavin mononucleotide, rebamipide, benfotiamine, olopatadine) calculated by the MMGBSA method is less than -35 kcal/mol. Thehighest probability of penetration through the blood-brain barrier, predicted by the ADMET web server, for the Olopatadine (at 17%) and Benfotiamine (at 12%).

Thus, as a result of the study, potential pharmacological chaperones of GC were selected from an expanded database of approved drugs for use, the ability of which to increase its enzymatic activity, as well as to reduce the level of the HexSph substrate requires further study.

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