Abstract
Deficiency or loss of function of Retinoblastoma-associated proteins (RbAp48) is related with Alzheimer's disease (AD), and AD disease is associated with age-related memory loss. During normal function, RbAp48 forms a complex with the peptide FOG-1 (friend of GATA-1) and has a role in gene transcription, but an unstable complex may affect the function of RbAp48. This study utilizes the world's largest traditional Chinese medicine (TCM) database and virtual screening to provide potential compounds for RbAp48 binding. A molecular dynamics (MD) simulation was employed to understand the variations after protein-ligand interaction. FOG1 was found to exhibit low stability after RbAp48 binding; the peptide displayed significant movement from the initial docking position, a phenomenon which matched the docking results. The protein structure of the other TCM candidates was not variable during MD simulation and had a greater stable affinity for RbAp48 binding than FOG1. Our results reveal that the protein structure does not affect ligand binding, and the top three TCM candidates Bittersweet alkaloid II, Eicosandioic acid, and Perivine might resolve the instability of the RbAp48-FOG1 complex and thus be used in AD therapy.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease to occur in people around the ages of 65 to 69 years [1], but it is not a normal part of aging and younger people may suffer from AD disease [2,3,4], these cases are not common
Research of computer-aided drug design (CADD) and traditional Chinese medicine (TCM) has been performed in many studies, such as influenza therapy [26,27,28], stroke prevention [29, 30], treatment of erectile dysfunction [31], reducing weight [32, 33], type II diabetes therapy [34], diseases associated with aging treatment [35], inflammation inhibitors development [36], HIV treatment [22], Parkinson’s disease prevention [37], and cancer therapy [12, 38, 39]
From ADMET and docking analysis, our candidates are determined to be more drugs-like than FOG1, and the three scoring functions -PMF, -PMF04, and Dock Score are higher than the control
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease to occur in people around the ages of 65 to 69 years [1], but it is not a normal part of aging and younger people may suffer from AD disease [2,3,4], these cases are not common. Presenilin 1 and presenilin 2 (PS1 and PS2) enhance the processing of transmembrane APP cleaved by alpha and beta proteases and gamma-secretases to form beta-amyloid 42 [8], which subsequently results in the development of AD In curing this disease, in animal models, antiamyloid therapies were used to clear amyloid accumulation. Research of CADD and TCM has been performed in many studies, such as influenza therapy [26,27,28], stroke prevention [29, 30], treatment of erectile dysfunction [31], reducing weight [32, 33], type II diabetes therapy [34], diseases associated with aging treatment [35], inflammation inhibitors development [36], HIV treatment [22], Parkinson’s disease prevention [37], and cancer therapy [12, 38, 39]. We present a small molecule from the world’s largest TCM database [40] to bind to RbAp48 and provide a more potent compound for target protein (RbAp48) binding than FOG-1
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