Computational Prediction for Precision Drug Discovery Against LRRK2 and GBA in Parkinson’s Disease

Parkinson’s disease (PD) is a degenerative neurological condition affecting the nervous system and the body’s nerve-controlled regions. There are several chemicals like 6-hydroxydopamine (6-OHDA), paraquat and rotenone that can induce PD in various animal model systems. Amongst these, one of the most common chemicals found in herbicides such as Paraquat (PQ) showed a link associated between the incidences of PD to its level of exposure. In the present study, several tools were used to predict the physicochemical and pharmacokinetic properties of selected molecules that can be targeted towards treatment of PD. This research focuses on understanding the role of key genes LRRK2 (Leucine-rich repeat kinase 2), GBA (Glucocerebrosidase) and APOE4 encoding for apolipoprotein E (apoE) which on mutations lead to adverse effects in the body eventually contributing to PD. Through AutoDock of these three targets with 34 ligands it was found that tolcapone showed the best binding energy of −5.99 kcal/mol followed by natural compounds such as Resveratrol (−5.12 kcal/mol) and Curcumin (−4.49 kcal/mol). Although, synthetic drugs such as Metformin and Tolcapone showed binding energy of −7.88 kcal/mol and −7.62 kcal/mol respectively, natural compounds, Curcumin and Resveratrol showed binding energy of −7.13 kcal/mol and−6.49 kcal/mol respectively, close to synthetic drugs for GBA target. Curcumin and its derivatives docked to APOE4 showed binding energy ranging between −2.18 kcal/mol to −5.95 kcal/mol. ADME properties indicated that most of the compounds exhibited good bioavailability and leadlikeness. Potential Transdermal Administration indicated Foslevodopa to be a potential candidate due to its high negative log Kp value. Favorable PASS and SOM Predictions demonstrated that compounds with high Pa (>0.7) and low Pi (<0.5) are considered potential leads for Parkinson’s treatment. These studies show that natural compounds could serve as promising candidates towards treatment of PD.