Molecular docking, dynamics simulation and pharmacokinetic studies of <i>Cyperus articulatus</i> essential oil metabolites as inhibitors of <i>Staphylococcus aureus</i>

<i>Cyperus articulatus</i> has been extensively studied for its essential oil (EO), active components and antibacterial activities against a wide range of bacteria such as <i>Bacillus megaterium</i>, <i>Streptococcus pyogenes</i>, <i>Staphylococcus epidermidis</i>, <i>Escherichia coli</i> and <i>Staphylococcus aureus</i>. However, knowledge of the biomolecular interaction of the individual EO metabolites responsible for its inhibition activities is lacking. The multi-drug-resistant bacteria <i>S. aureus</i>, which is of prime concern, has been reported to be inhibited by <i>Cyperus articulatus</i> rhizome EO. The present work analyzed the molecular interactions of the major <i>Cyperus articulatus</i> rhizome EO metabolites with the target enzyme TyrRS of <i>S. aureus</i> and studied the conformational dynamics and stability of the protein-ligand complexes. Molecular docking studies of selected EO metabolites such as mustakone, longifolenaldehyde, cyperotundone, α-copaene, β-calacorene, α-calacorene and khusinol were conducted along with standard drug chloramphenicol for comparative analysis of their binding affinity with <i>S. aureus</i> TyrRS. The metabolites khusinol, mustakone, β-calacorene and α-calacorene generated comparable docking scores (−6.4, −6.2, −6.1 and −6.2 kcal/mol, respectively) with that of the drug chloramphenicol (−6.3 kcal/mol). Most EO metabolites did not exhibit H-bonding with the <i>S. aureus</i> TyrRS residues and were stabilized through pi-interactions. The MD simulation study illustrated that compounds like mustakone could effectively bind to the receptors of <i>S. aureus</i> TyrRS with high stability and integrity. Pharmacokinetic, drug-like properties and toxicity analysis of the EO metabolites supported the candidature of mustakone and khusinol as pharmacologically important antibacterial drug ingredients. The study envisaged the structural framework of the EO metabolites for antibacterial drug design. Communicated by Ramaswamy H. Sarma<i>具节莎草（Cyperus articulatus）</i>的精油（essential oil, EO）、活性成分及其对多种细菌的抗菌活性已被广泛研究，所针对的细菌包括<i>巨大芽孢杆菌（Bacillus megaterium）</i>、<i>化脓性链球菌（Streptococcus pyogenes）</i>、<i>表皮葡萄球菌（Staphylococcus epidermidis）</i>、<i>大肠埃希菌（Escherichia coli）</i>以及<i>金黄色葡萄球菌（Staphylococcus aureus）</i>。然而，目前对于其抗菌活性所依赖的单一精油代谢物的生物分子相互作用机制仍知之甚少。备受关注的多重耐药金黄色葡萄球菌（<i>S. aureus</i>）已被报道可被具节莎草根茎精油所抑制。本研究分析了具节莎草根茎精油主要代谢物与金黄色葡萄球菌靶标酪氨酰-tRNA合成酶（tyrosyl-tRNA synthetase, TyrRS）的分子相互作用，并探究了蛋白质-配体复合物的构象动态与稳定性。本研究针对选定的精油代谢物（包括穆斯塔酮、长叶烯醛、莎草酮、α-古巴烯、β-卡拉油烯、α-卡拉油烯以及岩兰草醇）开展了分子对接研究，并以标准药物氯霉素（chloramphenicol）作为对照，对比分析它们与金黄色葡萄球菌TyrRS的结合亲和力。岩兰草醇、穆斯塔酮、β-卡拉油烯以及α-卡拉油烯所产生的对接得分（分别为-6.4、-6.2、-6.1和-6.2 kcal/mol）与氯霉素（-6.3 kcal/mol）的对接得分相当。大多数精油代谢物并未与金黄色葡萄球菌TyrRS的氨基酸残基形成氢键，而是通过π相互作用维持复合物的稳定。分子动力学（Molecular Dynamics, MD）模拟研究表明，穆斯塔酮等化合物可与金黄色葡萄球菌TyrRS有效结合，且复合物具有较高的稳定性与结构完整性。对精油代谢物的药代动力学、成药性及毒性分析结果表明，穆斯塔酮与岩兰草醇具备开发为具有药理学价值的抗菌药物成分的潜力。本研究为抗菌药物设计提供了精油代谢物的结构参考框架。本文由Ramaswamy H. Sarma转交刊发。