design of new candidates of pyrazole pyrimidinone as inhibitors of phosphodiesterase 5 (pde5) effective in the treatment of alzheimers by combining qsar and docking methods

Abstract: alzheimer’s disease (ad), characterized by a progressive impairment of memory and recognition, is a major health problem in both developing and developed countries. currently, no drugs can reverse the progression of ad. phosphodiesterase 5 (pde5) is a critical component of cyclic guanosine monophosphate/protein kinase g(cgmp/pkg) signaling pathway in neurons, the inhibition of which has produced neuroprotective effects, and pde5 inhibitors have recently been thought to be potential therapeutic agents for ad [1]. in this study, a novel quantitative structure_activity relationship (qsar) for inhibition activity against pde5 was performed based on molecularly docked structures of 43 pyrazole pyrimidinone derivatives [2]. molecular docking study was carried out for finding the best conformer of compounds which have suitable interaction with 1tbf protein. this structure was used in qsar study. qsar method can provide adequate information for understanding the role of pyrazole pyrimidinone derivatives for alzheimer disease. qsar models were developed by the stepwise-mlr, stepwise-ann, ga-ann, gsa-mlr and gsa-ann methods. the nonlinear gsa-ann model was selected as the best model, which includes mats5e, mats8p, mor06e, g3p, ish and psa descriptors. in validation process [3, 4], the model exhibited satisfactory statistical parameters (r2train=0.914, r2test=0.898, r2loo=0.771, r2l5o=0.772 and r2rand=0.239). in the next step, a series of pyrazol pyrimidinone derivatives were proposed as effective drugs for alzheimer disease. using the gsa-ann selected model, the activity (ic50) of newly designed compounds were predicted. among the proposed compounds, five compounds were selected as active compounds and introduced as candidates for new anti-alzheimers drugs.