Do Halogen-Hydrogen Bond Donor Interactions Dominate the Favorable Contribution of Halogens to Ligand-Protein Binding?
Do Halogen-Hydrogen Bond Donor Interactions Dominate the Favorable Contribution of Halogens to Ligand-Protein Binding?
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DOI：
10.1021/acs.jpcb.7b04198
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发表时间：
2017-07-20
期刊：
影响因子：
--
通讯作者：
MacKerell AD Jr
中科院分区：
文献类型：
--
作者：
Lin FY;MacKerell AD Jr
卤素存在于大量药物中，有利于配体-蛋白质结合。目前，卤素的贡献，最值得注意的是氯和溴，在很大程度上归因于卤键，涉及与氢键受体的有利相互作用。然而，我们表明，卤素作为氢键受体可能比卤素键的基础上量子力学计算配体结合作出更有利的贡献。此外，配体-蛋白质晶体结构的生物信息学分析显示存在大量的这种相互作用。结果表明，卤素与氢键给体（HBD）之间的相互作用以垂直的C-X···HBD取向为主。值得注意的是，卤素-HBD（X-HBD）相互作用的取向依赖性在大于100°时最小，有利的相互作用能范围为−2至−14 kcal/mol。这与卤素键形成对比，因为X-HBD相互作用实质上更有利，与典型氢键相当，具有较小的取向依赖性，使得它们对配体-蛋白质结合做出显著的有利贡献，因此，在合理的配体设计期间应积极考虑。
Halogens are present in a significant number of drugs, contributing favorably to ligand–protein binding. Currently, the contribution of halogens, most notably chlorine and bromine, is largely attributed to halogen bonds involving favorable interactions with hydrogen bond acceptors. However, we show that halogens acting as hydrogen bond acceptors potentially make a more favorable contribution to ligand binding than halogen bonds based on quantum mechanical calculations. In addition, bioinformatics analysis of ligand–protein crystal structures shows the presence of significant numbers of such interactions. It is shown that interactions between halogens and hydrogen bond donors (HBDs) are dominated by perpendicular C–X···HBD orientations. Notably, the orientation dependence of the halogen–HBD (X–HBD) interactions is minimal over greater than 100° with favorable interaction energies ranging from −2 to −14 kcal/mol. This contrasts halogen bonds in that X–HBD interactions are substantially more favorable, being comparable to canonical hydrogen bonds, with a smaller orientation dependence, such that they make significant, favorable contributions to ligand–protein binding and, therefore, should be actively considered during rational ligand design.
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影响因子：
62.1
作者：
Cavallo G;Metrangolo P;Milani R;Pilati T;Priimagi A;Resnati G;Terraneo G
通讯作者：
Terraneo G
影响因子：
2.9
作者：
Panigrahi, Sunil K.;Desiraju, Gautam R.
通讯作者：
Desiraju, Gautam R.
影响因子：
4.4
作者：
Peterson, KA;Figgen, D;Dolg, M
通讯作者：
Dolg, M
影响因子：
3.8
作者：
Brammer, L;Bruton, EA;Sherwood, P
通讯作者：
Sherwood, P
影响因子：
5.5
作者：
Jorgensen, William L.;Schyman, Patric
通讯作者：
Schyman, Patric