Alturki Mansour S, Alkhodier Reem A, Gomaa Mohamed S, Hussein Dania A, Tawfeeq Nada, Al Khzem Abdulaziz H, Pottoo Faheem H, Albugami Shmoukh A, Aldawsari Mohammed F, Rants'o Thankhoe A
Department of Pharmaceutical Chemistry, College of Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
Department of Pharmaceutical Sciences, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia.
Int J Mol Sci. 2025 Jun 26;26(13):6131. doi: 10.3390/ijms26136131.
The development of orally bioavailable non-peptidomimetic glucagon-like peptide-1 receptor agonists (GLP-1RAs) offers a promising therapeutic avenue for the treatment of type 2 diabetes mellitus (T2DM) and obesity. An extensive in silico approach combining structure-based drug design and ligand-based strategies together with pharmacokinetic properties and drug-likeness predictions is implemented to identify novel non-peptidic GLP-1RAs from the COCONUT and Marine Natural Products (CMNPD) libraries. More than 700,000 compounds were screened by shape-based similarity filtering in combination with precision docking against the orthosteric site of the GLP-1 receptor (PDB ID: 6X1A). The docked candidates were further assessed with the molecular mechanics MM-GBSA tool to check the binding affinities; the final list of candidates was validated by running a 500 ns long MD simulation. Twenty final hits were identified, ten from each database. The hits contained compounds with reported antidiabetic effects but with no evidence of GLP-1 agonist activity, including hits , , , and . These findings proposed a novel mechanism for these hits through GLP-1 activity and positioned the other hits as potential promising scaffolds. Among the studied compounds-especially hits , , and -possessed strong and stable interactions with critical amino acid residues such as TRP-203, PHE-381, and GLN-221 at the active site of the 6X1A-substrate along with favorable pharmacokinetic profiles. Moreover, the RMSF and RMSD plots further suggested the possibility of stable interactions. Specifically, hit possessed the best docking score with a ΔG_bind value of -102.78 kcal/mol, surpassing even the control compound in binding affinity. The ADMET profiling also showed desirable drug-likeness and pharmacokinetic characteristics for hit . The pipeline of computational integration underscores the potential of non-peptidic alternatives in natural product libraries to pursue GLP-1-mediated metabolic therapy into advanced preclinical validation.
口服生物可利用的非肽模拟胰高血糖素样肽-1受体激动剂（GLP-1RAs）的开发为2型糖尿病（T2DM）和肥胖症的治疗提供了一条有前景的治疗途径。实施了一种广泛的计算机辅助方法，将基于结构的药物设计和基于配体的策略与药代动力学性质及类药性预测相结合，以从COCONUT和海洋天然产物（CMNPD）库中鉴定新型非肽类GLP-1RAs。通过基于形状的相似性筛选结合针对GLP-1受体正构位点（PDB ID：6X1A）的精确对接，对70多万种化合物进行了筛选。对接的候选物进一步用分子力学MM-GBSA工具评估以检查结合亲和力；通过运行500纳秒的长分子动力学模拟对候选物的最终列表进行验证。确定了20个最终命中物，每个数据库10个。这些命中物包含有报道的抗糖尿病作用但无GLP-1激动剂活性证据的化合物，包括命中物 、 、 和 。这些发现通过GLP-1活性为这些命中物提出了一种新机制，并将其他命中物定位为潜在的有前景的骨架。在所研究的化合物中，尤其是命中物 、 和 与6X1A底物活性位点的关键氨基酸残基如TRP-203、PHE-381和GLN-221具有强而稳定的相互作用，同时具有良好的药代动力学特征。此外，RMSF和RMSD图进一步表明了稳定相互作用的可能性。具体而言，命中物 具有最佳对接分数，ΔG_bind值为-102.78 kcal/mol，其结合亲和力甚至超过对照化合物。ADMET分析也显示命中物 具有理想的类药性和药代动力学特征。计算整合流程强调了天然产物库中非肽替代物在将GLP-1介导的代谢疗法推进到高级临床前验证方面的潜力。
