In silico molecular targets, docking, dynamics simulation and physiologically based pharmacokinetics modeling of oritavancin.

IF 2.8 3区 医学 Q2 PHARMACOLOGY & PHARMACY BMC Pharmacology & Toxicology Pub Date : 2024-10-22 DOI:10.1186/s40360-024-00804-z
Toluwase Hezekiah Fatoki, Tosin Christianah Balogun, Adebayo Emmanuel Ojewuyi, Aduragbemi Christianah Omole, Oluwaseun Victor Olukayode, Afolasade Precious Adewumi, Adanne Joy Umesi, Nwadinma Priscillia Ijeoma, Abibat Esther Apooyin, Chinecherem Perpetual Chinedu, Ibukun Esther Idowu, Momoh Jimoh Isah
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Abstract

Introduction: Oritavancin is a semi-synthetic lipoglycopeptide antibiotic primarily used to treat serious infections caused by Gram-positive bacteria. The aim of this study was to elucidate possible molecular targets of oritavancin in human and microbes in relevance to its mechanism of action and model its pharmacokinetics for optimal dose selection in clinical practice.

Methods: Computational methods were used in this study which include target prediction, molecular docking, molecular dynamics simulation, pharmacokinetics prediction, and physiological-based pharmacokinetics (PBPK) modeling.

Results: Oritavancin was moderately soluble in water and did not permeate the blood-brain barrier. Seven molecular targets were identified in humans. Molecular docking results showed highest binding affinity of oritavancin with PI3-kinase p110-gamma subunit (-10.34 kcal/mol), followed by Acyl-CoA desaturase (-10.07 kcal/mol) and Cytochrome P450 2C19 (-8.384 kcal/mol). Oritavancin PBPK modelling in adult human showed that infusion has lower peak concentrations (Cmax) compared to bolus administration, with 1200 mg dose yielded Cmax of 16.559 mg/L, 800 mg dose yielded Cmax of 11.258 mg/L, and 200 mg over 3 days dose yielded Cmax of 7.526 mg/L. Notably, infusion gave extended half-life (t1/2) for all doses and slightly higher clearance rates compared to bolus, particularly for the 1200 mg and 800 mg doses. The results corroborated existing clinical pharmacokinetic data, and confirmed the model's accuracy and predictive capability.

Conclusion: This comprehensive computational study has provided invaluable insights into the pharmacological profile of Oritavancin, aiding its further development and optimization for clinical use.

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奥利他万星的分子靶标、对接、动力学模拟和基于生理学的药代动力学建模。
简介奥立他万星(Oritavancin)是一种半合成脂甘肽抗生素,主要用于治疗革兰氏阳性菌引起的严重感染。本研究旨在阐明奥利他万星在人类和微生物中可能存在的分子靶点与其作用机制的相关性,并建立其药代动力学模型,以便在临床实践中选择最佳剂量:本研究采用的计算方法包括靶点预测、分子对接、分子动力学模拟、药代动力学预测和基于生理的药代动力学(PBPK)建模:结果:奥立他万星中度溶于水,不透过血脑屏障。在人体中发现了七个分子靶点。分子对接结果显示,奥立他万星与 PI3 激酶 p110-gamma 亚基的结合亲和力最高(-10.34 kcal/mol),其次是 Acyl-CoA desaturase(-10.07 kcal/mol)和细胞色素 P450 2C19(-8.384 kcal/mol)。奥立万星在成人体内的 PBPK 模型显示,输注的峰值浓度(Cmax)低于栓剂给药,1200 毫克剂量的 Cmax 为 16.559 毫克/升,800 毫克剂量的 Cmax 为 11.258 毫克/升,200 毫克 3 天剂量的 Cmax 为 7.526 毫克/升。值得注意的是,与静脉注射相比,输注可延长所有剂量的半衰期(t1/2),清除率也略高,尤其是 1200 毫克和 800 毫克剂量。结果证实了现有的临床药代动力学数据,并确认了模型的准确性和预测能力:这项全面的计算研究为了解奥立万星的药理学特征提供了宝贵的见解,有助于进一步开发和优化其临床应用。
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
BMC Pharmacology & Toxicology
BMC Pharmacology & Toxicology PHARMACOLOGY & PHARMACYTOXICOLOGY&nb-TOXICOLOGY
CiteScore
4.80
自引率
0.00%
发文量
87
审稿时长
12 weeks
期刊介绍: BMC Pharmacology and Toxicology is an open access, peer-reviewed journal that considers articles on all aspects of chemically defined therapeutic and toxic agents. The journal welcomes submissions from all fields of experimental and clinical pharmacology including clinical trials and toxicology.
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