Planejamento de inibidores triplos frente à acetilcolinesterase, butirilcolinesterase e beta-secretase 1

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative chronical disorder that primarily affects the elderly. Despite impacts in patients’ life, current pharmacological treatments show limited efficacy, highlighting the urgent need for new therapeutic options. For this reason, multitarget compounds capable of simultaneously inhibiting key enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase 1 (BACE-1) have emerged as promising candidates and, in regard of multitarget identification, drug repurposing has proven to be an effective strategy. Previous virtual screening identified silodosin, an FDA-approved drug for treat urological conditions, as a potential triple inhibitor for AD treatment (QFIT=31.67; ScoreAChE=-8.0kcal/mol; ScoreBuChE=-8.1kcal/mol; ScoreBACE-1=-43.55). This study evaluated silodosin and its derivatives using in vitro assays and molecular dynamics (MD) simulations. Silodosin was shown to be safe at concentrations below 10μM, with low AChE inhibition (IC₅₀>500μM) but satisfactory activity against BuChE and BACE-1. MD simulations confirmed these findings, revealing greater complex stability with BuChE and BACE-1. Rational design of new derivatives led to improved AChE affinity, with structural modifications such as simplification of the linker chain and introduction of smaller substituents. Derivative S23 demonstrated a promising binding profile (ScoreAChE =-9.8kcal/mol; ScoreBuChE=-7.7kcal/mol; ScoreBACE-1=- 39.74) and was selected for synthesis and further evaluation. These findings support the viability of the multi-target approach and contribute to the development of new therapeutic candidates for AD.