Gomaa Mohamed S, Alturki Mansour S, Tawfeeq Nada, Hussein Dania A, Pottoo Faheem H, Al Khzem Abdulaziz H, Sarafroz Mohammad, Abubshait Samar
Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
Pharmaceutics. 2024 Dec 17;16(12):1607. doi: 10.3390/pharmaceutics16121607.
Glucagon-like peptide-1 (GLP-1) receptor is currently one of the most explored targets exploited for the management of diabetes and obesity, with many aspects of its mechanisms behind cardiovascular protection yet to be fully elucidated. Research dedicated towards the development of oral GLP-1 therapy and non-peptide ligands with broader clinical applications is crucial towards unveiling the full therapeutic capacity of this potent class of medicines. This study describes the virtual screening of a natural product database consisting of 695,133 compounds for positive GLP-1 allosteric modulation. The database, obtained from the Coconut website, was filtered according to a set of physicochemical descriptors, then was shape screened against the crystal ligand conformation. This filtered database consisting of 26,325 compounds was used for virtual screening against the GLP-1 allosteric site. The results identified ten best hits with the XP score ranging from -9.6 to -7.6 and MM-GBSA scores ranging from -50.8 to -32.4 and another 58 hits from docked pose filter and a second round of XP docking and MM-GBSA calculation followed by molecular dynamics. The analysis of results identified hits from various natural products (NPs) classes, to whom attributed antidiabetic and anti-obesity effects have been previously reported. The results also pointed to β-lactam antibiotics that may be evaluated in drug repurposing studies for off-target effects. The calculated ADMET properties for those hits revealed suitable profiles for further development in terms of bioavailability and toxicity. The current study identified several NPs as potential GLP-1 positive allosteric modulators and revealed common structural scaffolds including peptidomimetics, lactams, coumarins, and sulfonamides with peptidomimetics being the most prominent especially in indole and coumarin cores.
胰高血糖素样肽-1（GLP-1）受体是目前治疗糖尿病和肥胖症研究最多的靶点之一，其心血管保护机制的许多方面尚待充分阐明。致力于开发口服GLP-1疗法和具有更广泛临床应用的非肽类配体的研究，对于揭示这类强效药物的全部治疗能力至关重要。本研究描述了对一个由695,133种化合物组成的天然产物数据库进行虚拟筛选，以寻找GLP-1正变构调节剂。从Coconut网站获得的该数据库，根据一组物理化学描述符进行筛选，然后针对晶体配体构象进行形状筛选。这个由26,325种化合物组成的经过筛选的数据库，用于针对GLP-1变构位点进行虚拟筛选。结果确定了十个最佳命中物，其XP分数范围为-9.6至-7.6，MM-GBSA分数范围为-50.8至-32.4，另外通过对接姿势筛选以及第二轮XP对接和MM-GBSA计算，随后进行分子动力学，又确定了58个命中物。结果分析确定了来自各种天然产物（NP）类别的命中物，之前已有报道称这些类别具有抗糖尿病和抗肥胖作用。结果还指出了β-内酰胺类抗生素，可在药物重新利用研究中对其脱靶效应进行评估。对这些命中物计算的ADMET性质显示出在生物利用度和毒性方面适合进一步开发的特征。当前研究确定了几种NP作为潜在的GLP-1正变构调节剂，并揭示了常见的结构支架，包括拟肽、内酰胺、香豆素和磺酰胺，其中拟肽最为突出，尤其是在吲哚和香豆素核心结构中。
