Contents lists available at ScienceDirect Chemical Physics Letters journal homepage: www.elsevier.com/locate/cplett Research paper Proposal of therapeutic curcumin derivatives for Alzheimer’s disease based on ab initio molecular simulations Tomoki Shinzato a , Riku Sato a , Katsumi Suzuki a , Shogo Tomioka a , Haruki Sogawa a , Sergiy Shulga b , Yaroslav Blume b , Noriyuki Kurita a, ⁎ a Department of Computer Science and Engineering, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan b Institute for Food Biotechnology and Genomics, National Academy of Sciences of Ukraine, 2a. Osypovskogo Str., Kyiv-123 04123, Ukraine HIGHLIGHTS • Specific interactions between Aβ and its inhibitors were theoretically studied. • The interactions were precisely investigated by ab initio molecular simulations. • Some derivatives of curcumin-I were proposed as a novel inhibitor against Aβ. • Curcumin-Ib has larger binding energy to Aβ than the existing inhibitors. ARTICLE INFO Keywords: Alzheimer’s disease Amyloid-β Aggregation Drug design Inhibitor Fragment molecular orbital Protein and ligand docking Moleculr mechanics Curcumin ABSTRACT Aggregation of amyloid-β peptides (Aβs) in a brain is deeply involved in the onset of Alzheimer’s disease, and various agents inhibiting the aggregation have been developed based on natural substances to suppress the onset. We here proposed novel curcumin derivatives as potent inhibitors against the aggregation and in- vestigated their binding properties to Aβ, using protein-ligand docking and ab initio fragment molecular orbital methods. The results reveal that a curcumin derivative, in which COH 3 group of the aromatic ring is replaced by OH, binds strongly to Aβ and can be a potent inhibitor against the Aβ aggregation. 1. Introduction Alzheimer’s disease (AD) has been one of major diseases in recent medical science. AD is a neurodegenerative disease characterized by senile plaques on the surface of the cerebral cortex and neurofibrillary tangles in a brain, and the cognitive function of the brain is remarkably decreased by AD [1–3]. The previous experiments [2,4–6] revealed that main constituent of the senile plaques are amyloid-β peptides (Aβ), which are produced from the degradation of amyloid precursor protein (APP) by the β- and γ-secretase enzymes. It was also confirmed that Aβs in the senile plaques form various aggregates by their self-assembles [7–14]. A recent study on Aβ toxicity [15] has revealed that small so- luble aggregates are key to Aβ toxicity, while the dimers impair sy- naptic plasticity in mouse hippocampal slices, and the monomers de- void of neurotoxicity. In addition, a significant correlation was found between the Aβ toxicity and the binding to neuronal cells of Aβ trimer and tetramer, but not monomer or dimer [16]. Since the aggregation of Aβs is considered to be the first step in the onset of AD, inhibition of the aggregation is expected to be effective for treating ADs [17]. Therefore, it is expected that the compounds with higher binding affinity to Aβ can be effective for preventing the ag- gregation of Aβs and treating ADs [18]. For example, natural sub- stances such as quercetin (contained in onion), EGCG (contained in green tea), apigenin (contained in celery) and curcumin-I (contained in turmeric) were proposed as the candidate inhibitors against the Aβ aggregation, and their effects were investigated [19–21]. In particular, curcumin-I and its derivatives are known to be prime candidates for inhibiting the aggregation [22]. Accordingly, there are plenty of docking simulations of curcumin derivatives to Aβ [23,24], in order to propose novel derivatives as a potent inhibitor against the Aβ https://doi.org/10.1016/j.cplett.2019.136883 Received 26 July 2019; Received in revised form 16 October 2019; Accepted 18 October 2019 ⁎ Corresponding author. E-mail address: kurita@cs.tut.ac.jp (N. Kurita). Chemical Physics Letters xxx (xxxx) xxxx 0009-2614/ © 2019 Elsevier B.V. All rights reserved. Please cite this article as: Tomoki Shinzato, et al., Chemical Physics Letters, https://doi.org/10.1016/j.cplett.2019.136883