Oselusi Samson O, Sibuyi Nicole Rs, Martin Darius R, Meyer Mervin, Madiehe Abram M
Nanobiotechnology Research Group, Department of Biotechnology, University of the Western Cape, Private Bag X17, Bellville, Cape Town, 7535, South Africa; DSI/Mintek Nanotechnology Innovation Centre (NIC), Biolabels Research Node, Department of Biotechnology, University of the Western Cape, Private Bag X17, Bellville, Cape Town, 7535, South Africa.
DSI/Mintek Nanotechnology Innovation Centre (NIC), Biolabels Research Node, Department of Biotechnology, University of the Western Cape, Private Bag X17, Bellville, Cape Town, 7535, South Africa; Health Platform, Advanced Materials Division, Mintek, 200 Malibongwe Drive, Randburg, South Africa.
Comput Biol Med. 2025 Feb;185:109487. doi: 10.1016/j.compbiomed.2024.109487. Epub 2024 Dec 4.
Matrix metalloproteinases (MMPs) serve as prognostic factors in several pathophysiological conditions, including chronic wounds. Therefore, they are considered important therapeutic targets in the intervention and treatment of these conditions. In this study, computational tools such as molecular docking and molecular dynamics simulations were used to gain insight into protein‒ligand interactions and determine the free binding energy between Ehretia species phytoconstituents and gelatinases (MMP2 and MMP9). A total of 74 phytoconstituents from Ehretia species were compiled from the literature, and 46 of these compounds were identified as potential inhibitors of at least one type of MMP. Molecular docking revealed that lithospermic acid B, rosmarinic acid, and danshensu had stronger binding affinities against the two enzymes than the reference ligands. Furthermore, (9S, 10E, 12Z, 15Z)-9-hydroxy-10,12,15-octadecatrienoic (∗-octadecatrienoic) had a higher binding energy for MMP2, whereas caffeic anhydride and caffeic acid established stronger binding energy with MMP9 than the reference ligand. These complexes also demonstrated relatively stable, favourable, and comparable conformational changes with those of unbound proteins at 500 ns. The free energy decomposition results further provide detailed insights into the contributions of active site residues and different types of interactions to the overall binding free energy. Finally, most of the hit phytoconstituents (rosmarinic acid, caffeic anhydride, caffeic acid, and danshensu) had good physicochemical, drug-likeness, and pharmacokinetic properties. Collectively, our findings showed that phytoconstituents from Ehretia species could be beneficial in the search for novel MMP inhibitors as therapeutic agents for the treatment of chronic wounds.
基质金属蛋白酶（MMPs）在包括慢性伤口在内的多种病理生理状况中作为预后因素。因此，它们被认为是这些状况干预和治疗中的重要治疗靶点。在本研究中，使用了诸如分子对接和分子动力学模拟等计算工具来深入了解蛋白质-配体相互作用，并确定厚壳树属植物化学成分与明胶酶（MMP2和MMP9）之间的自由结合能。从文献中收集了厚壳树属植物的总共74种植物化学成分，其中46种化合物被鉴定为至少一种MMP的潜在抑制剂。分子对接显示，紫草酸B、迷迭香酸和丹参素对这两种酶的结合亲和力比参考配体更强。此外，（9S，10E，12Z，15Z）-9-羟基-10,12,15-十八碳三烯酸（* - 十八碳三烯酸）对MMP2具有更高的结合能，而咖啡酸酐和咖啡酸与MMP9形成的结合能比参考配体更强。在500 ns时，这些复合物与未结合蛋白相比也表现出相对稳定、有利且可比的构象变化。自由能分解结果进一步详细揭示了活性位点残基和不同类型相互作用对整体结合自由能的贡献。最后，大多数命中的植物化学成分（迷迭香酸、咖啡酸酐、咖啡酸和丹参素）具有良好的物理化学性质、类药性质和药代动力学性质。总体而言，我们的研究结果表明，厚壳树属植物的植物化学成分可能有助于寻找新型MMP抑制剂作为治疗慢性伤口的治疗药物。
