Li Hong, Komori Akari, Li Mingdi, Chen Xiaomei, Yang Angela Wei Hong, Sun Xiaomin, Liu Yanyan, Hung Andrew, Zhao Xiaoshan, Zhou Lin
Department of Traditional Chinese Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China.
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
J Mol Liq. 2023 Mar 15;374:121253. doi: 10.1016/j.molliq.2023.121253. Epub 2023 Jan 16.
Combination drugs have been used for several diseases for many years since they produce better therapeutic effects. However, it is still a challenge to discover candidates to form a combination drug. This study aimed to investigate whether using a comprehensive in silico approach to identify novel combination drugs from a Chinese herbal formula is an appropriate and creative strategy. We, therefore, used Toujie Quwen Granules for the main protease (M) of SARS-CoV-2 as an example. We first used molecular docking to identify molecular components of the formula which may inhibit M. Baicalein (HQA004) is the most favorable inhibitory ligand. We also identified a ligand from the other component, cubebin (CHA008), which may act to support the proposed HQA004 inhibitor. Molecular dynamics simulations were then performed to further elucidate the possible mechanism of inhibition by HQA004 and synergistic bioactivity conferred by CHA008. HQA004 bound strongly at the active site and that CHA008 enhanced the contacts between HQA004 and M. However, CHA008 also dynamically interacted at multiple sites, and continued to enhance the stability of HQA004 despite diffusion to a distant site. We proposed that HQA004 acted as a possible inhibitor, and CHA008 served to enhance its effects via allosteric effects at two sites. Additionally, our novel wavelet analysis showed that as a result of CHA008 binding, the dynamics and structure of M were observed to have more subtle changes, demonstrating that the inter-residue contacts within M were disrupted by the synergistic ligand. This work highlighted the molecular mechanism of synergistic effects between different herbs as a result of allosteric crosstalk between two ligands at a protein target, as well as revealed that using the multi-ligand molecular docking, simulation, free energy calculations and wavelet analysis to discover novel combination drugs from a Chinese herbal remedy is an innovative pathway.
由于联合用药能产生更好的治疗效果，多年来一直被用于多种疾病的治疗。然而，发现能够组成联合用药的候选药物仍然是一项挑战。本研究旨在探讨使用全面的计算机模拟方法从中药配方中识别新型联合用药是否是一种合适且具有创新性的策略。因此，我们以透解祛瘟颗粒对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的主要蛋白酶（M）的作用为例。我们首先使用分子对接来识别该配方中可能抑制M的分子成分。黄芩苷（HQA004）是最有利的抑制性配体。我们还从另一种成分荜澄茄脂素（CHA008）中鉴定出一种配体，它可能起到支持所提出的HQA004抑制剂的作用。然后进行分子动力学模拟，以进一步阐明HQA004的可能抑制机制以及CHA008赋予的协同生物活性。HQA004在活性位点强烈结合，并且CHA008增强了HQA004与M之间的接触。然而，CHA008也在多个位点动态相互作用，并且尽管扩散到远处位点仍继续增强HQA004的稳定性。我们提出HQA004可能作为一种抑制剂，而CHA008通过在两个位点的变构效应来增强其作用。此外，我们新颖的小波分析表明，由于CHA008的结合，观察到M的动力学和结构有更细微的变化，表明M内的残基间接触被协同配体破坏。这项工作突出了由于蛋白质靶点上两个配体之间的变构串扰而导致不同草药之间协同效应的分子机制，同时也揭示了使用多配体分子对接、模拟、自由能计算和小波分析从中药中发现新型联合用药是一条创新途径。
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