Computational evaluation of small molecule inhibitors of RGS4 to regulate the dopaminergic control of striatal LTD

Abstract

Parkinson’s disease is a neurodegenerative disease which is the result of the degradation of the dopaminergic neurons in the substantia nigra pars compacta, leading to a disregulation of thalamocortical circuits. Traditional treatment involves the use of levodopa which increases the dopamine level in the striatum. There is a need for alternative non-dopamine therapy to prevent the side effects of the conventional drugs used. Recently small molecule inhibitors of RGS have become the prime candidates in studies related to regulating RGS by binding to its allosteric site and thus changing its structure. Through the docking studies we observed that these small molecule modulators of RGS4 make stable complexes with RGS4 when compared to native RGS4. The Gq(alpha)–GS4–rug complexes are less stable. The increase in flexibility of the RGS4–rug complex could be the reason for the inability of the RGS4–rug complex to bind to the G protein. In our docking results, CCG63802 formed the most promising drug as a RGS4 inhibitor as it formed the most stable complex with RGS4 and also formed the least stable complex, Gq(alpha)–RGS4–CCG63802 complex. In our studies we evaluated the therapeutic potential of the small molecule inhibitors to provide a prospective treatment for Parkinson’s disease.

Keywords: RGS4 inhibitor; Parkinson disease; Flexibility; MGlu receptors; Neural plasticity

The Egyptian Journal of Medical Human Genetics (2013) 14, 135–142