QM/QM docking method based on the variational finite localized molecular orbital approximation.
We present a derivation of the semiempirical variational finite localized molecular orbital (VFL) approximation, which was introduced by Anikin et al. (J Chem Phys 2004, 121, 1266). On the basis of VFL approximation, we developed the novel semiempirical (quantum mechanical) QM/QM method in which a part of the system, including the ligand and protein active site, are treated self-consistently, while the protein bulk is considered as carrying a frozen electronic density matrix. The developed method is applied toward the QM docking study for the p56 LCK SH2 domain. The virtual search has predicted 10 most potent inhibitors by searching through the database of 200,000 empirically docked poses of 20,000 drug-like molecules. Energy score calculation of each complex roughly consisting of 1700 atoms took 14.54 s of single-CPU time at the NDDO AM1 level. The entire computation performed on a 32-CPU cluster would be accomplished in 1 day. Flexible ligand QM docking studies, performed on a subset of 10,000 poses, required 153.03 s of single-CPU time per complex. The entire calculation performed on the 32-CPU cluster would be finished in half-day.
Anisimov
Victor M
VM
FQS Poland Ltd., Starowislna 13, Krakow 31-038, Poland. v.anisimov@fqs.pl
Bugaenko
Vladislav L
VL
D020134:Catalytic Domain; D008024:Ligands; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D011506:Proteins / Q000737:chemistry*; D011789:Quantum Theory; D013816:Thermodynamics; D018909:src Homology Domains
D008024:Ligands; D011506:Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)