Virtual screening of drugs against multiple targets of Alzheimer's disease
Abstract
BackgroundDrug repurposing offers a rapid, cost-effective approach for discovering therapies against multiple targets.ObjectiveHere, we screen virtual ligand libraries consisting of 3468 approved drugs against 11 protein targets associated with Alzheimer's disease (AD).MethodsWe employ blind molecular docking, and target amyloid-β (Aβ), microtubule-associated protein tau (MAPT), Apolipoprotein E4 (APOE4), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), amyloid-β protein precursor (AβPP), β-secretase (BACE1), brain-derived neurotrophic factor (BDNF), presenilin 1 (PSEN1) and 2 (PSEN2), and α-synuclein (SNCA) proteins using AutoDock Vina.ResultsNotably, multitarget binding recurs among the top-10 ligands with Ergotamine and Dihydroergotamine potentially binding 8; Dutasteride 7; Drospirenone and Nilotinib 6; Adapalene and Conivaptan 5; Bromocriptine 4; and Rolapitant, Irinotecan, Plerixafor, Saquinavir, and Telmisartan 3, out of 11 protein targets. As such, we reveal potential binding sites for ergot alkaloids, steroids, retinoids, antivirals, angiotensin receptor blockers, and Neurokinin 1 (NK1) receptor antagonists on multiple AD targets. Importantly, the therapeutic potential of the top-scoring ligands is confounded by pharmacokinetics and adverse-effects. For example, poor blood-brain barrier (BBB) penetration, and vasoconstriction, discount ergot-alkaloid use in AD. Likewise, potential toxicity limits prolonged use of steroids, Nilotinib, Adapalene, and…
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