Đanić Maja, Pavlović Nebojša, Zaklan Dragana, Stanimirov Bojan, Lazarević Slavica, Al-Salami Hani, Mikov Momir
Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
Front Pharmacol. 2024 Dec 3;15:1492284. doi: 10.3389/fphar.2024.1492284. eCollection 2024.
Gliclazide, a second-generation sulfonylurea derivative still widely used as a second-line treatment for type 2 diabetes mellitus, is well known to be subject to interindividual differences in bioavailability, leading to variations in therapeutic responses among patients. Distinct gut microbiota profiles among individuals are one of the most crucial yet commonly overlooked factors contributing to the variable bioavailability of numerous drugs. In light of the shift towards a more patient-centered approach in diabetes treatment, this study aimed to conduct a pharmacoinformatic analysis of gliclazide metabolites produced by gut microbiota and assess their docking potential with the SUR1 receptor to identify compounds with improved pharmacological profiles compared to the parent drug.
Ten potential gliclazide metabolites produced by the gut microbiota were screened for their pharmacological properties. Molecular docking analysis regarding SUR1 receptor was performed using Molegro Virtual Docker software. Drug-likeness properties were evaluated using DruLiTo software. Subsequently, the physicochemical and pharmacokinetic properties of gliclazide and its metabolites were determined by using VolSurf+ software package.
All studied metabolites exhibited better intrinsic solubility than gliclazide, which is of interest, considering that solubility is a limiting factor for its bioavailability. Based on the values of investigated molecular descriptors, hydroxylated metabolites M1-M6 showed the most pronounced polar and hydrophilic properties, which could significantly contribute to their solubility. Additionally, docking analysis revealed that four hydroxyl-metabolites (M1, M3, M4, and M5), although having a slightly poorer permeability through the Caco-2 cells compared to gliclazide, showed the highest binding affinity to the SUR1 receptor and exhibited the most suitable pharmacological properties.
study revealed that hydroxylated gut microbiota-produced gliclazide metabolites should be further investigated as potential drug candidates with improved characteristics compared to parent drug. Moreover, their part in the therapeutic effects of gliclazide should be additionally studied , in order to elucidate the role of gut microbiota in gliclazide pharmacology, namely from the perspective of personalized medicine.
格列齐特作为第二代磺脲类衍生物，至今仍被广泛用作2型糖尿病的二线治疗药物。众所周知，其生物利用度存在个体差异，导致患者间治疗反应各异。个体间不同的肠道微生物群谱是导致众多药物生物利用度变化的最关键但常被忽视的因素之一。鉴于糖尿病治疗正朝着更以患者为中心的方法转变，本研究旨在对肠道微生物群产生的格列齐特代谢产物进行药物信息学分析，并评估它们与SUR1受体的对接潜力，以确定与母体药物相比具有改善药理特性的化合物。
筛选出肠道微生物群产生的10种潜在格列齐特代谢产物的药理特性。使用Molegro Virtual Docker软件对SUR1受体进行分子对接分析。使用DruLiTo软件评估类药性质。随后，使用VolSurf+软件包确定格列齐特及其代谢产物的物理化学和药代动力学性质。
所有研究的代谢产物均表现出比格列齐特更好的固有溶解度，考虑到溶解度是其生物利用度的限制因素，这一点很有意义。根据所研究分子描述符的值，羟基化代谢产物M1 - M6表现出最明显的极性和亲水性质，这可能显著有助于它们的溶解度。此外，对接分析表明，四种羟基代谢产物（M1、M3、M4和M5），尽管与格列齐特相比通过Caco - 2细胞的渗透性略差，但对SUR1受体显示出最高的结合亲和力，并表现出最合适的药理特性。
研究表明，与母体药物相比，肠道微生物群产生的羟基化格列齐特代谢产物作为具有改善特性的潜在候选药物应进一步研究。此外，应进一步研究它们在格列齐特治疗效果中的作用，以阐明肠道微生物群在格列齐特药理学中的作用，即从个性化医学的角度。
