Drug target interaction energies by the kernel energy method in aminoglycoside drugs and ribosomal A site RNA targets
Drug target interaction energies by the kernel energy method in aminoglycoside drugs and ribosomal A site RNA targets
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DOI：
10.1073/pnas.0610533104
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发表时间：
2007-03-13
影响因子：
11.1
通讯作者：
Karle, Jerome
中科院分区：
文献类型：
--
作者：
Huang, Lulu;Massa, Lou;Karle, Jerome
利用从头算量子力学的全部能量来研究药物与其分子靶标的相互作用是可能的。这个想法直到最近才被实现，因为众所周知，随着分子中原子数量的研究，使用量子力学的计算难度增加了。由于药物化学中的生化分子往往很大，包含数千个甚至数万个原子，全量子问题的计算难度一直令人望而却步。然而，有两件事改变了这一观点：(I)并行超级计算机的进步，以及(Ii)被称为量子结晶学的量子形式主义的发现，以及量子核的使用，这是一种非常适合并行计算的方法。这些进展将使量子力学从头计算多肽、蛋白质、DNA和RNA的分子能量，获得高精度的结果。在这种方法中，表示一个分子的计算难度只会随着原子数量的增加而略有增加。通过采用一个可接受的近似来简化计算，该近似允许用更小的原子核来表示完整的生物分子。这些结果表明，药物化学的问题，如药物的合理设计，可以通过量子力学分析来解释。一般情况是通过具体的例子来说明的，即三种氨基糖苷类药物的HF/STO-3G计算，它们附着在核糖体A位RNA核苷酸靶标上。
It is possible to use the full power of ab initio quantum mechanics in application to the interaction of drugs and their molecular targets. This idea had barely been realized until recently, because of the well known growth in computational difficulty of the use of quantum mechanics, with the number of atoms in the molecule to be studied. Because the biochemical molecules of medicinal chemistry are so often large, containing thousands or even tens of thousands of atoms, the computational difficulty of the full quantum problem had been prohibitive. Two things have happened, however, that change this perspective: (i) the advances of parallel supercomputers, and (ii) the discovery of a quantum formalism called quantum crystallography and the use of quantum kernels, a method that is well suited for parallel computation. Such advances would allow the quantum mechanical ab initio calculation of the molecular energy of peptides, proteins, DNA, and RNA, obtaining results of high accuracy. In this approach the computational difficulty of representing a molecule increases only modestly with the number of atoms. The calculations are simplified by adopting an acceptable approximation that allows a full biological molecule to be represented by smaller "kernels" of atoms. These results suggest that problems of medicinal chemistry, such as the rational design of drugs, may be illuminated by quantum mechanical analysis. The general case is illustrated by specific examples, namely, the HF/STO-3G calculations of three aminoglycoside drugs that attach to ribosomal A-site RNA nucleotide targets.