The vitamin D receptor (VDR) constitutes a promising therapeutic target for the treatment of cancer. Unfortunately, its natural agonist calcitriol does not have clinical utility due to its potential to induce hypercalcemic effects at the concentrations required to display antitumoral activity. For this reason, the search for new calcitriol analogues with adequate therapeutic profiles has been actively pursued by the scientific community. We have previously reported the obtaining and the biological activity evaluation of new calcitriol analogues by modification of its sidechain, which exhibited relevant antiproliferative and selectivity profiles against tumoral and normal cells. In this work we conducted molecular modeling studies (i.e. molecular docking, molecular dynamics, constant pH molecular dynamics (CpHMD) and free energy of binding analysis) to elucidate at an atomistic level the molecular basis related to the potential of the new calcitriol analogues to achieve selectivity between tumoral and normal cells. Two histidine residues (His305 and His397) were found to exhibit a particular tautomeric configuration that produces the observed bioactivity. Also, different acid-based properties were observed for His305 and His307 with His305 showing an increased acidity (pKa 5.2) compared to His397 (pKa 6.8) and to the typical histidine residue. This behavior favored the pharmacodynamic interaction of the calcitriol analogues exhibiting selectivity for tumoral cells when VDR was modeled at the more acidic tumoral environment (pH ≅ 6) compared to the case when VDR was modeled at pH 7.4 (normal cell environment). On the other hand, non-selective compounds, including calcitriol, exhibited a similar interaction pattern with VDR when the receptor was modeled at both pH conditions. The results presented constitute the first evidence on the properties of the VDR receptor in different physicochemical environments and thus represent a significant contribution to the in silico screening and design of new calcitriol analogues.

中文翻译：

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维生素D受体在肿瘤和正常微环境中表现出不同的药效学特征：一项分子模型研究。

维生素D受体（VDR）构成了治疗癌症的有希望的治疗靶标。不幸的是，由于其天然的激动剂骨化三醇在显示抗肿瘤活性所需的浓度下具有诱导高钙血症作用的潜力，因此没有临床用途。由于这个原因，科学界一直在积极寻求具有足够治疗特性的新钙三醇类似物。我们以前曾报道过通过修饰其侧链获得新的骨化三醇类似物并对其进行生物学活性评估，该侧链显示出针对肿瘤和正常细胞的相关抗增殖和选择性特征。在这项工作中，我们进行了分子建模研究（即分子对接，分子动力学，恒定pH分子动力学（CpHMD）和结合能的自由能），以原子水平阐明与新型骨化三醇类似物在肿瘤细胞和正常细胞之间实现选择性的潜力有关的分子基础。发现两个组氨酸残基（His305和His397）显示出产生所观察到的生物活性的特定互变异构构型。而且，对于His305和His307，观察到不同的基于酸的性质，与His397（pKa 6.8）和典型的组氨酸残基相比，His305显示出增加的酸度（pKa 5.2）。当在较酸性的肿瘤环境（pH≅6）下模拟VDR时，与在pH 7.4时（正常细胞环境）下模拟VDR时相比，这种行为有利于骨三醇类似物对肿瘤细胞具有选择性的药效相互作用。另一方面，当在两个pH条件下模拟受体时，包括骨化三醇在内的非选择性化合物与VDR的相互作用模式相似。提出的结果构成了VDR受体在不同物理化学环境中特性的第一个证据，因此对计算机筛选和设计新的三醇类似物具有重要意义。