Computational profiling of terpenoids for putative dual-target leads against Staphylococcus aureus penicillin binding protein 2a and beta-lactamase: An integrated structure-activity-relationship-based study

IF 5.2 2区化学 Q2 CHEMISTRY, PHYSICAL

Journal of Molecular Liquids Pub Date : 2025-10-05 DOI:10.1016/j.molliq.2025.128617

Gideon Ampoma Gyebi, Saheed Sabiu

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引用次数: 0

Abstract

In Staphylococcus aureus, the penicillin-binding protein (PBP2a) and beta-lactamase (β-LTM) are primarily implicated in resistance to beta-lactam antibiotics, making them essential targets for the development of novel therapeutics. Terpenoids have proven to be a valuable source of antibiotics owing to their diversity, ability to target multiple bacterial pathways, and relatively low toxicity profiles. Herein, by employing a methodical blend of structure-based pharmacophore modelling, molecular docking, and ensemble-based docking analysis, five lead terpenoids (beta-amyrin, conferone, feselol, lantanolic acid, and quinovic acid) with higher binding tendencies for S. aureus PBP2a and β-LTM active sites, as well as the PBP2a allosteric site, were identified from a compiled library of 147,953 terpenoids. These leads also presented favourable in silico pharmacokinetic characteristics, drug likeness, and ADMET profiles. The thermostability investigation of the resulting complexes of the leads over a 180-ns molecular dynamics simulation revealed enhanced structural stability in the bound state. Relative to the reference standards, ceftaroline (−41.50 ± 6.11 kcal/mol) and clavulanate (−21.40 ± 4.7 kcal/mol), the most potent lead, quinovic acid (−47.09 ± 6.08 kcal/mol) against S. aureus PBP2a, as well as lantanolic acid (−35.35 ± 3.25 kcal/mol) and quinovic acid (−28.48 ± 4.99 kcal/mol) against S. aureus β-LTM, exhibited superior binding free energy, respectively. The principal component analysis (PCA) revealed more constrained motions in the bound structures compared to a wider range of conformational states in the unbound structures. Furthermore, quinovic acid, while being stabilised in the allosteric site of PBP2a, caused higher mobility of the gatekeeper residue, Tyr446, thereby suggesting an “opening” of the active site for therapeutic targeting. The favourable molecular orbital energies of the leads further suggest them as putative candidates to be further explored as therapeutics against multidrug-resistant S. aureus infections. Validatory studies are underway.

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针对金黄色葡萄球菌青霉素结合蛋白2a和β -内酰胺酶的假定双靶标萜类化合物的计算分析：一项基于结构-活性关系的综合研究

在金黄色葡萄球菌中，青霉素结合蛋白（PBP2a）和β-内酰胺酶（β-LTM）主要与β-内酰胺类抗生素的耐药性有关，这使它们成为开发新疗法的重要靶点。萜类化合物由于其多样性、针对多种细菌途径的能力以及相对较低的毒性，已被证明是一种有价值的抗生素来源。本文采用基于结构的药效团建模、分子对接和基于集成的对接分析方法，从已编译的147,953个萜类化合物文库中鉴定出5个对金黄色葡萄球菌PBP2a和β-LTM活性位点以及PBP2a变构位点具有较高结合倾向的铅萜类化合物（β- amyrin、松果酮、羊甾醇、镧醛酸和喹啉酸）。这些线索也显示了有利的硅药代动力学特征，药物相似性和ADMET谱。在180-ns分子动力学模拟中，对引线配合物的热稳定性进行了研究，发现在结合状态下结构稳定性增强。与对照品相比，头孢他林（- 41.50±6.11 kcal/mol）和克拉维酸（- 21.40±4.7 kcal/mol）对金黄色葡萄球菌PBP2a的抑制作用最强，喹啉酸（- 47.09±6.08 kcal/mol）对金黄色葡萄球菌β-LTM的抑制作用最强，兰薄荷酸（- 35.35±3.25 kcal/mol）和喹啉酸（- 28.48±4.99 kcal/mol）对金黄色葡萄球菌β-LTM的抑制作用最强。主成分分析（PCA）表明，与非束缚结构相比，束缚结构的约束运动更多。此外，奎诺维奇酸虽然稳定在PBP2a的变张位点，但却导致了看门者残基Tyr446的高流动性，从而提示了活性位点的“开放”，可以用于治疗靶向。这些先导物良好的分子轨道能量进一步表明，它们作为抗耐多药金黄色葡萄球菌感染的候选药物值得进一步探索。验证性研究正在进行中。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Molecular Liquids 化学-物理：原子、分子和化学物理

CiteScore

10.30

自引率

16.70%

发文量

2597

审稿时长

78 days

期刊介绍： The journal includes papers in the following areas: – Simple organic liquids and mixtures – Ionic liquids – Surfactant solutions (including micelles and vesicles) and liquid interfaces – Colloidal solutions and nanoparticles – Thermotropic and lyotropic liquid crystals – Ferrofluids – Water, aqueous solutions and other hydrogen-bonded liquids – Lubricants, polymer solutions and melts – Molten metals and salts – Phase transitions and critical phenomena in liquids and confined fluids – Self assembly in complex liquids.– Biomolecules in solution The emphasis is on the molecular (or microscopic) understanding of particular liquids or liquid systems, especially concerning structure, dynamics and intermolecular forces. The experimental techniques used may include: – Conventional spectroscopy (mid-IR and far-IR, Raman, NMR, etc.) – Non-linear optics and time resolved spectroscopy (psec, fsec, asec, ISRS, etc.) – Light scattering (Rayleigh, Brillouin, PCS, etc.) – Dielectric relaxation – X-ray and neutron scattering and diffraction. Experimental studies, computer simulations (MD or MC) and analytical theory will be considered for publication; papers just reporting experimental results that do not contribute to the understanding of the fundamentals of molecular and ionic liquids will not be accepted. Only papers of a non-routine nature and advancing the field will be considered for publication.