Bashant Madeline M, Mitchell Saige M, Hart Lucy R, Lebedenko Charlotta G, Banerjee Ipsita A
Department of Chemistry, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA.
J Mol Model. 2021 Dec 28;28(1):16. doi: 10.1007/s00894-021-05007-5.
In this work, we designed three new ligands by conjugating cholesterol metabolites 3-hydroxy-5-cholestenoic acid (3-HC) and 3-oxo-4-cholestenoic acid (3-OC) and the natural tri-terpenoid betulinic acid with the tumor-targeting peptide YHWYGYTPQNVI. Molecular interactions with the unconjugated peptide and the conjugates were examined with three receptors that are commonly overexpressed in pancreatic adenocarcinoma cells using ligand docking and molecular dynamics. This study demonstrated the utility of the designed conjugates as a valuable scaffold for potentially targeting EGFR and LDLR receptors. Our results indicate that the conjugates showed strong binding affinities and formation of stable complexes with EGFR, while the unconjugated peptide, BT-peptide conjugate, an 3-HC-peptide conjugate showed the formation of fairly stable complexes with LDLR receptor. For EGFR, two receptor kinase domains were explored. Interactions with the N-terminal domain of CCKA-R were relatively weaker. For LDLR, binding occurred in the beta-propeller region. For the N-terminal fragment of CCKA-R, the conjugates induced significant conformational changes in the receptor. The molecular dynamic simulations for 100 ns demonstrate that BT-peptide conjugates and the unconjugated peptide had the highest binding and formed the most stable complexes with EGFR. RMSD and trajectory analyses indicate that these molecules transit to a dynamically stable configuration in most cases within 60 ns. NMA analysis indicated that amongst the conjugates that showed relatively higher interactions with the respective receptors, the highest potential for deformability was seen for the N-terminal-47 amino acid region of the CCKA-R receptor with and the lowest for the LDLR-receptor. Thus, the newly designed compounds may be evaluated in the future toward developing drug delivery materials for targeting tumor cells overexpressing LDLR or EGFR.
在这项工作中，我们通过将胆固醇代谢产物3-羟基-5-胆甾烯酸（3-HC）和3-氧代-4-胆甾烯酸（3-OC）以及天然三萜类桦木酸与肿瘤靶向肽YHWYGYTPQNVI偶联，设计了三种新的配体。使用配体对接和分子动力学方法，研究了未偶联肽和偶联物与胰腺腺癌细胞中通常过度表达的三种受体的分子相互作用。这项研究证明了所设计的偶联物作为潜在靶向表皮生长因子受体（EGFR）和低密度脂蛋白受体（LDLR）的有价值支架的实用性。我们的结果表明，偶联物与EGFR显示出很强的结合亲和力并形成稳定的复合物，而未偶联肽、桦木酸-肽偶联物和3-HC-肽偶联物与LDLR受体形成了相当稳定的复合物。对于EGFR，研究了两个受体激酶结构域。与胆囊收缩素A受体（CCKA-R）N端结构域的相互作用相对较弱。对于LDLR，结合发生在β-螺旋桨区域。对于CCKA-R的N端片段，偶联物诱导受体发生显著的构象变化。100纳秒的分子动力学模拟表明，桦木酸-肽偶联物和未偶联肽与EGFR具有最高的结合力并形成最稳定的复合物。均方根偏差（RMSD）和轨迹分析表明，这些分子在大多数情况下在60纳秒内转变为动态稳定构型。正常模态分析（NMA）表明，在与各自受体表现出相对较高相互作用的偶联物中，CCKA-R受体N端47个氨基酸区域的可变形性潜力最高，而LDLR受体的可变形性潜力最低。因此，新设计的化合物未来可用于评估开发靶向过度表达LDLR或EGFR的肿瘤细胞的药物递送材料。
