A fast method of large-scale serial semiempirical calculations of docking complexes

Abstract

A brief survey of the state of the art in methods of calculations of protein-ligand interaction energies in docking complexes is presented. A new computational technique is proposed that allows one to fundamentally improve the performance of large scale serial calculations of docking complexes using the AM1/PM3 semiempirical methods. The technique explicitly al lows for a specific feature of docking problems, viz., the need for calculating numerous ligand complexes with a specified protein whose noninteracting part remains "frozen" during computa tions. The interaction energies calculated using the new method differ only slightly from the results of complete АМ1 calculations and the performance attained is high enough to solve practical drug design problems.Key words: large scale calculations of docking complexes, fast quantum chemical calcula tions, semiempirical methods.The determination of activity of relatively small ligand molecules (prototypes of active principles of drugs) in the interaction with large protein molecules is a key problem in biochemistry. Knowledge of energies of the interaction of a protein with ligands for very large ligand collections is of crucial importance for efficient targeted drug design. Meanwhile, the design of pharmaceuticals including high ly specific and even individually "tuned" ones (in the fu ture) belongs to scientific challenges of crucial importance.It is appropriate to begin large scale preliminary screening of ligands to choose best candidates from the standpoint of ligand-protein interactions with theo retical studies using computer simulation followed by more expensive and long term experiments with the ligands chosen.The increasing use of computer assisted docking* is due to important role of this technique for novel drug de sign technologies. The demand of rapidly developing phar maceutical industry for less expensive drug design, which becomes increasingly more complicated 1 against the back ground of exponentially increasing computer performance, makes the docking (or, more generally, computer assisted * From this point on we use the term "docking" in a broad sense including the determination of ligand arrangement in the protein cavity and the energy of the protein-ligand interaction.

Quantum Mechanics in Structure‐Based Ligand Design

“…Although it is possible to study at least small proteins with DFT methods, [101] all linearscaling whole-protein studies of ligand binding have been performed at the semiempirical level, AM1, PM3, PM5, or PM6-DH2. [102,103,104,105,106,107,108,109,110,111,112] This approach was pioneered by Merz and coworkers. They studied 18 carbonic anhydrase and 5 carboxypeptidase inhibitors with the AM1 method, using their D&C approach.…”

“…Anikin et al have developed a semiempirical QM approach to study the special case when many ligands are docked to a fixed protein structure, using a fixed density of the protein. [107] Using only the pure QM energy, they dock 1783 ligands with 30-144 atoms to the FKBP-12 protein with an average time consumption of only 5 minutes per ligand. With a similar approach, 200 000 poses of 20 000 ligands were docked to the p56 LCK SH2 domain.…”

Ligand-Binding Affinity Estimates Supported by Quantum-Mechanical Methods

“…Anikin et al have suggested a method to rescore many docked structures, speeding up the calculations by taking advantage of the fact that many ligands are docked to the same rigid part of the protein. 303 They employed the AM1 and PM3 methods and showed that the method works well, but did not compare the results to experimental data. With this approach the binding energy of each protein−ligand complex could be obtained in 5 min.…”

Fully ab initio protein‐ligand interaction energies with dispersion corrected density functional theory

“…They have been applied to docking and scoring studies frequently at the semiempirical level of theory. [18–25] However, as was shown before for PL interaction energies of truncated PL models,[26] to obtain their high performance level, semiempirical methods sacrifice their overall accuracy. Linear scaling approaches enable to perform correlated quantum chemical calculations for macromolecular systems, too.…”