This chapter focuses on various computation methodologies successfully applied in CNS drug discovery processes, such as design of novel donepezil–indolyl hybrids, N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl) propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, and donepezil-pyridyl hybrids, as multitarget inhibitors of acetylcholine esterase and MAO (AChE/BuChE/MAO-A/MAO-B) that were effective drug candidates for therapy of neurodegenerative Alzheimer's (AD) and Parkinson's diseases (PD). The gene discussed is ACHE; the disease is Parkinson disease.