Novel 3D pharmacophore of α-MSH/γ-MSH hybrids leads to selective human MC1R and MC3R analogues
Novel 3D pharmacophore of α-MSH/γ-MSH hybrids leads to selective human MC1R and MC3R analogues
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DOI：
10.1021/jm049579s
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发表时间：
2005-03-24
影响因子：
7.3
通讯作者：
Hruby, VJ
中科院分区：
文献类型：
--
作者：
Cai, MY;Mayorov, AV;Hruby, VJ
为了进一步评估可能有助于γ-MSH的3D拓扑结构的元素，我们系统地设计了一组线性γ-MSH类似物并评估了它们的生物活性：没有N-末端乙酰基，有和没有C-末端酰胺，有Nle（3），有L-或D-Phe（6）或D-Nal（2 '）（6），以及有D-Trp（8）或D-Nal（2 '）（8）。发现将γ-MSH中的C-末端酸改变为酰胺并用Nle替代Met导致在黑皮质素受体的所有四种亚型处的结合亲和力增加（10-100倍）。在γ-MSH-NH 2中用D-Nal（2 '）（8）取代Trp（8）和用D-Phe（6）取代Phe（6）形成hMC 3R的选择性拮抗剂，而在γ-MSH-NH 2处用D-Nal（2 '）（6）取代Phe（6）和用D-Trp（8）取代Trp（8）产生hMC 1 R的选择性部分激动剂。最后，在γ-MSH-NH 2中用Pro（5）取代HiS（5）和用D-Nal（2 '）（8）取代Trp（8）导致hMC 1 R的高度有效和选择性激动剂。分子模拟显示，在Nle（3）-γ-MSH-NH 2的C-末端，存在逆转样结构，表明可能存在参与γ-MSH类似物的配体-受体相互作用的次级结合位点，这可以解释Nle（3）-γ-MSH-NH 2类似物的结合亲和力增强。我们的结果表明，增加疏水性和用更大的芳香族氨基酸残基取代Phe（6）和Trp（8）对于α-MSH/γ-MSH杂合体对hMCR的选择性是非常重要的。
To further evaluate elements that could contribute to the 3D topographical structure of gamma-MSH, we have systematically designed a group of linear gamma-MSH analogues and evaluated their biological activities: without a N-terminal acetyl, with and without a C-terminal amide, with Nle(3), with L- or D-Phe(6) or D-Nal(2 ')(6), and with D-Trp(8) or D-Nal(2 ')(8). It was found that changing the C-terminal acid in gamma-MSH to an amide and replacing Met with Nle leads to increased binding affinities at all four subtypes of melanocortin receptors (10-100 fold). Substitution of Trp(8) with D-Nal(2 ')(8) and Phe(6) with D-Phe(6) in gamma-MSH-NH2 forms a selective antagonist for the hMC3R, whereas, substitution of Phe(6) with D-Nal(2 ')(6) and replacing Trp(8) with D-Trp(8) at gamma-MSH-NH2 yields a selective partial agonist for the hMC1R. Finally, substitution of HiS(5) with Pro(5) and Trp(8) with D-Nal(2 ')(8) in gamma-MSH-NH2 leads to a highly potent and selective agonist for the hMC1R. Molecular modeling showed that, at the C-terminal of Nle(3)-gamma-MSH-NH2, there is a reverse-turn-like structure, suggesting that there might be a secondary binding site involved in ligand-receptor interaction for gamma-MSH analogues that may explain the enhanced binding affinities of the Nle(3)-gamma-MSH-NH2 analogues. Our results indicate that increasing the hydrophobicity and replacing Phe(6) and Trp(8) with bulkier aromatic amino acid residues is very important for selectivity of alpha-MSH/gamma-MSH hybrids for hMCRs.