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>砖子苗（Cyperus articulatus）</i>的精油（EO）、活性成分及其对多种细菌的抗菌活性已得到广泛研究，受试细菌包括<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>大肠杆菌（Escherichia coli）</i>与<i>金黄色葡萄球菌（Staphylococcus aureus）</i>。然而，目前对于该精油中赋予其抗菌活性的单一代谢物的生物分子相互作用机制仍知之甚少。 作为重点关注的多重耐药菌，<i>金黄色葡萄球菌（S. aureus）</i>已被证实可被砖子苗根茎精油抑制。本研究分析了砖子苗根茎精油主要代谢物与<i>金黄色葡萄球菌</i>靶标酶酪氨酰-tRNA合成酶（TyrRS）的分子相互作用，并探究了蛋白质-配体复合物的构象动力学与稳定性。 本研究对所选精油代谢物——包括香附子酮（mustakone）、长叶烯醛（longifolenaldehyde）、莎草酮（cyperotundone）、α-古巴烯（α-copaene）、β-卡拉油烯（β-calacorene）、α-卡拉油烯（α-calacorene）以及岩兰草醇（khusinol）——开展了分子对接研究，并以标准药物氯霉素（chloramphenicol）作为对照，以比较其与<i>金黄色葡萄球菌</i> TyrRS的结合亲和力。 结果显示，岩兰草醇、香附子酮、β-卡拉油烯与α-卡拉油烯的对接得分分别为-6.4、-6.2、-6.1与-6.2 kcal/mol，与氯霉素的对接得分（-6.3 kcal/mol）相当。多数精油代谢物未与<i>金黄色葡萄球菌</i> TyrRS残基形成氢键相互作用，而是通过π相互作用维持复合物稳定。 分子动力学（MD）模拟研究表明，香附子酮等化合物可与<i>金黄色葡萄球菌</i> TyrRS受体有效结合，且复合物具备较高的稳定性与结构完整性。对精油代谢物的药代动力学、类药性质与毒性分析结果证实，香附子酮与岩兰草醇具备成为具有药理学意义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框架。本文由Ramaswamy H. Sarma通讯发表。