Marshall Trevor G, Lee Robert E, Marshall Frances E
Autoimmunity Research Foundation, Thousand Oaks, California 91360, USA.
Theor Biol Med Model. 2006 Jan 10;3:1. doi: 10.1186/1742-4682-3-1.
There have been indications that common Angiotensin Receptor Blockers (ARBs) may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1,25-dihydroxyvitamin-D. This receptor mediates the expression of regulators as ubiquitous as GnRH (Gonadatrophin hormone releasing hormone) and the Parathyroid Hormone (PTH). Additionally we examined Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma), which affects the function of phagocytic cells, and the C-CChemokine Receptor, type 2b, (CCR2b), which recruits monocytes to the site of inflammatory immune challenge.
Telmisartan was predicted to strongly antagonize (Ki asymptotically equal to 0.04 nmol) the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki asymptotically equal to10 nmol) are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki asymptotically equal to 30 nmol) and Losartan (Ki asymptotically equal to 70 nmol) may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki asymptotically equal to 0.3 nmol), while Losartan (Ki asymptotically equal to 3 nmol), Irbesartan (Ki asymptotically equal to 6 nmol), Olmesartan and Valsartan (Ki asymptotically equal to 12 nmol) also seem likely to have significant PPAR modulatory activity. Olmesartan and Irbesartan (Ki asymptotically equal to 9 nmol) additionally act as antagonists of a theoretical model of CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the Angiotensin II Type1 receptor (AT2R1) has been presented.
Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the activation of two key nuclear receptors-VDR and PPARgamma. If our simulations are confirmed by experiment, it is possible that ARBs may become useful as potent anti-inflammatory agents, in addition to their current indication as cardiovascular drugs.
有迹象表明,常见的血管紧张素受体阻滞剂(ARB)可能通过直接调节免疫系统发挥抗炎作用。我们决定使用分子建模来快速评估哪些潜在靶点值得进行详细的实验室验证。我们首先研究了维生素D受体(VDR)核受体,它由类固醇激素1,25 - 二羟基维生素D激活。该受体介导诸如促性腺激素释放激素(GnRH)和甲状旁腺激素(PTH)等广泛存在的调节因子的表达。此外,我们还研究了过氧化物酶体增殖物激活受体γ(PPARγ),它影响吞噬细胞的功能,以及C - C趋化因子受体2b(CCR2b),它将单核细胞招募到炎症免疫挑战部位。
预测替米沙坦能强烈拮抗(Ki渐近等于0.04 nmol)VDR。ARB中的奥美沙坦、厄贝沙坦和缬沙坦(Ki渐近等于10 nmol)在典型的体内浓度下可能是有用的VDR拮抗剂。坎地沙坦(Ki渐近等于30 nmol)和氯沙坦(Ki渐近等于70 nmol)也可能有效抑制VDR。替米沙坦是PPARγ的强调节剂(Ki渐近等于0.3 nmol),而氯沙坦(Ki渐近等于3 nmol)、厄贝沙坦(Ki渐近等于6 nmol)、奥美沙坦和缬沙坦(Ki渐近等于12 nmol)似乎也可能具有显著的PPAR调节活性。奥美沙坦和厄贝沙坦(Ki渐近等于9 nmol)还可作为CCR2b理论模型的拮抗剂。对该CCR2b模型进行了初步验证,并提出了血管紧张素II 1型受体(AT2R1)的模型。
分子建模已被证明对于生成关于受体/配体结合的可测试假设很有价值,并且是药物设计中的重要工具。ARB被设计用作AT2R1的拮抗剂,发现它们对结构相似的CCR2b具有亲和力并不奇怪。然而,这项研究还发现证据表明ARB可调节两个关键核受体——VDR和PPARγ的激活。如果我们的模拟得到实验证实,那么除了目前作为心血管药物的适应证外,ARB有可能成为有效的抗炎药物。