天然存在的异黄酮类化合物丰韵苷具有广泛的治疗应用，包括抗氧化、抗肿瘤、抗病毒、抗糖尿病和神经保护活性。然而，丰韵苷低水溶性限制了其在化妆品、保健品和制药行业的前景应用。环糊精（CDs），尤其是β-CD及其衍生物已成为提高难溶化合物水溶性形成包合物的有前途的剂型。我们采用多尺度（1000 ns）显式溶剂法和伞形采样分子动力学（MD）模拟研究丰韵苷和五种最常用的β-CD衍生物之间包合物形成的相互作用和热力学参数。经典MD模拟揭示了三种可能的丰韵苷在羟丙基-β-CD（HP-β-CD）、甲基化-β-CD（ME-β-CD）和磺丁烯基-β-CD（SBE-β-CD）中心腔内的结合构象。丰韵苷苯并吡喃环在β-CD衍生物中心腔内的结合构象比苯基占据疏水腔的构象更频繁。这些相互作用得到了各种非键接触，包括氢键、pi-孤对、pi-σ 和pi-烷基相互作用的支持。丰韵苷与所有所选的β-CD衍生物都显示出有利的最终状态MD驱动热力学结合自由能，除了琥珀酰-β-CD（S-β-CD）。此外，我们使用伞形采样模拟研究了宿主-客体包合物的相互作用和热力学参数。SBE-β-CD /丰韵苷包合物显示出最低的结合能，意味着在所有所选的宿主-客体包合物中具有最高的亲和力。我们的研究可用作分析和比较不同β-CD衍生物增强难溶分子水溶性能力的标准。版权所有© 2023 Elsevier Ltd。保留所有权利。

Formononetin, a naturally occurring isoflavone exhibits a wide range of therapeutic applications including antioxidant, anti-tumor, antiviral, anti-diabetic and neuroprotective activities. However, the low hydro-solubility of formononetin has limited its prospective use in cosmetic, neutraceutical and pharmaceutical industries. Cyclodextrins (CDs), especially β-CD and its derivatives have emerged as promising agents to improve the water solubility of poorly hydrosoluble compounds by the formation of inclusion complexes. We employed multiscale (1000 ns) explicit solvent and umbrella sampling molecular dynamics (MD) simulations to study the interactions and thermodynamic parameters of inclusion complex formation between formononetin and five most commonly used β-CD derivatives. Classical MD simulations revealed two possible binding conformations of formononetin inside the central cavity of hydroxypropyl-β-CD (HP-β-CD), randomly methylated-β-CD (ME-β-CD), and sulfobutylether-β-CD (SBE-β-CD). The binding conformation with the benzopyrone ring of formononetin inside the central cavity of β-CD derivatives was more frequent than the phenyl group occupying the hydrophobic cavity. These interactions were supported by a variety of non-bonded contacts including hydrogen bonds, pi-lone pair, pi-sigma, and pi-alkyl interactions. Formononetin showed favorable end-state MD-driven thermodynamic binding free energies with all the selected β-CD derivatives, except succinyl-β-CD (S-β-CD). Furthermore, umbrella sampling simulations were used to investigate the interactions and thermodynamic parameters of the host-guest inclusion complexes. The SBE-β-CD/formononetin inclusion complex showed the lowest binding energy signifying the highest affinity among all the selected host-guest inclusion complexes. Our study could be used as a standard for analyzing and comparing the ability of different β-CD derivatives to enhance the hydro-solubility of poorly soluble molecules.Copyright © 2023 Elsevier Ltd. All rights reserved.