Drug target interaction energies by the kernel energy method in aminoglycoside drugs and ribosomal A site RNA targets.

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.