Author Description

Parkinson’s disease is the most common movement disorder affecting 1% of people older than 60 years. Rivastigmine is a pseudo-irreversible, carbamate type-brain selective, dual Ache-BuChE inhibitor is used for mild to moderate PD and it has less side effects compared to levodopa. For developing a ligand based analogue for Rivastigmine, CADD and GOLD docking is used. In this work, the binding modes of the putative/proposed inhibitors were obtained by carefully aligning them with the known crystal structures of inhibitors in the active site of the 1GQR. These inhibitors, which are shown in the above Figures, were then evaluated by performing minimization calculations both in solvent and in complex using the MM+ force field. The technical details used for estimating relative binding affinities using energy components obtained from minimizations of each inhibitor, both in solvent as well as in complex phases, were explained by four stage protocol as described in the in-methodology section. A comparison of the relative binding affinities for structurally similar Inhibitors to Rivastigmine indicates that the molecular mechanics methods gave suitable analogues. These results clearly indicate that before synthesis and biochemical testing of new analogues, one can use molecular mechanics-based methods for qualitative assessment of relative binding affinities for speeding up drug discovery process by eliminating less potent compounds from synthesis. The inhibitor with the substituent R=CCl3 (-63.608208) is identified as the most suitable analogues in the present study need to be further evaluated in laboratory.