Pereira Alfredo, Valdés-Muñoz Elizabeth, Marican Adolfo, Cabrera-Barjas Gustavo, Vijayakumar Sekar, Valdés Oscar, Rafael Diana, Andrade Fernanda, Abaca Paulina, Bustos Daniel, Durán-Lara Esteban F
Departamento de Química Orgánica y Fisicoquímica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380544, Chile.
Doctorado en Biotecnología Traslacional, Facultad de Ciencias Agrarias y Forestales, Escuela de Ingeniería en Biotecnología, Universidad Católica del Maule, Talca 3480094, Chile.
Pharmaceutics. 2023 Jan 31;15(2):474. doi: 10.3390/pharmaceutics15020474.
In light of the growing bacterial resistance to antibiotics and in the absence of the development of new antimicrobial agents, numerous antimicrobial delivery systems over the past decades have been developed with the aim to provide new alternatives to the antimicrobial treatment of infections. However, there are few studies that focus on the development of a rational design that is accurate based on a set of theoretical-computational methods that permit the prediction and the understanding of hydrogels regarding their interaction with cationic antimicrobial peptides (cAMPs) as potential sustained and localized delivery nanoplatforms of cAMP. To this aim, we employed docking and Molecular Dynamics simulations (MDs) that allowed us to propose a rational selection of hydrogel candidates based on the propensity to form intermolecular interactions with two types of cAMPs (MP-L and NCP-3a). For the design of the hydrogels, specific building blocks were considered, named monomers (MN), co-monomers (CM), and cross-linkers (CL). These building blocks were ranked by considering the interaction with two peptides (MP-L and NCP-3a) as receptors. The better proposed hydrogel candidates were composed of MN3-CM7-CL1 and MN4-CM5-CL1 termed HG1 and HG2, respectively. The results obtained by MDs show that the biggest differences between the hydrogels are in the CM, where HG2 has two carboxylic acids that allow the forming of greater amounts of hydrogen bonds (HBs) and salt bridges (SBs) with both cAMPs. Therefore, using theoretical-computational methods allowed for the obtaining of the best virtual hydrogel candidates according to affinity with the specific cAMP. In conclusion, this study showed that HG2 is the better candidate for future in vitro or in vivo experiments due to its possible capacity as a depot system and its potential sustained and localized delivery system of cAMP.
鉴于细菌对抗生素的耐药性不断增强，且缺乏新型抗菌药物的研发，在过去几十年中，人们开发了众多抗菌递送系统，旨在为感染的抗菌治疗提供新的选择。然而，很少有研究专注于基于一套理论计算方法进行合理设计的开发，这些方法能够预测和理解水凝胶与阳离子抗菌肽（cAMP）的相互作用，将其作为cAMP潜在的持续和局部递送纳米平台。为此，我们采用了对接和分子动力学模拟（MDs），这使我们能够根据与两种类型的cAMP（MP-L和NCP-3a）形成分子间相互作用的倾向，合理选择水凝胶候选物。在水凝胶的设计中，考虑了特定的构建模块，即单体（MN）、共聚单体（CM）和交联剂（CL）。通过将与两种肽（MP-L和NCP-3a）作为受体的相互作用进行排序，这些构建模块得以确定。提出的较好的水凝胶候选物分别由MN3-CM7-CL1和MN4-CM5-CL1组成，称为HG1和HG2。MDs获得的结果表明，水凝胶之间的最大差异在于CM，其中HG2有两个羧酸，能够与两种cAMP形成更多的氢键（HBs）和盐桥（SBs）。因此，使用理论计算方法能够根据与特定cAMP的亲和力获得最佳的虚拟水凝胶候选物。总之，本研究表明，由于HG2作为储存系统的潜在能力及其作为cAMP潜在的持续和局部递送系统的可能性，它是未来体外或体内实验的更好候选物。
