The Structural Basis of DL0410, a Novel Multi-Target Candidate Drug for the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a complicated disease for which there are still no ideal one-target drugs, while multi-target drugs are closer to ideal drugs and will provide new solutions for the clinical treatment of AD. DL0410 is a promising multi-target drug candidate for AD treatment that is not only a significant inhibitor against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) but also an antagonist of histamine H3 receptor (H3R), and its therapeutic efficacy in treating cognitive dysfunction has been validated in a series of AD-related animal models, including scopolamine-induced mice, D-galactose-induced and Aβ-induced mice, and APP/PS1 and SAMP8 mice. Although the structure of DL0410 has been analyzed using various detection techniques, such as MS and NMR, its three-dimensional crystal structure still requires further confirmation. In this study, the crystal of DL0410 was grown in aqueous solution, and its structure was detected using the X-ray diffraction method. The crystal data, atomic coordinates, bond lengths, angles, and hydrogen bonds of DL0410 were obtained. Its stability was proven by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Based on this study, the molecular docking of DL0410 with AChE, BuChE, and H3R was performed to uncover their interaction mechanisms and explain their bioactivities. This study provides important information for new multi-target drug design and the research and development of new drugs for AD treatment.