The ability of molecular docking, using the program Glide and an MM-GBSA postdocking scoring protocol, to correctly rank a number of congeneric kinase inhibitors was assessed. The approach was successful for the cases considered and suggests that this may be useful for the design of inhibitors in the lead optimization phase of drug discovery.
Key Points
AZD1208 is a selective pan-Pim kinase inhibitor with efficacy in AML cells, xenografts, and Flt3-internal tandem duplication or Flt3 wild-type patient samples. AML cell growth inhibition is associated with suppression of p70S6K, 4EBP1 phosphorylation, and messenger RNA translation.
Four of the most well-known, commercially available docking programs, FlexX, GOLD, GLIDE, and ICM, have been examined for their ligand-docking and virtual-screening capabilities. The relative performance of the programs in reproducing the native ligand conformation from starting SMILES strings for 164 high-resolution protein-ligand complexes is presented and compared. Applying only the native scoring functions, the latest versions of these four docking programs were also used to conduct virtual screening for 12 protein targets of therapeutic interest, involving both publicly available structures and AstraZeneca in-house structures. The capability of the four programs to correctly rank-order target-specific active compounds over alternative binders and nonbinders (decoys plus randomly selected compounds) and thereby enrich a small subset of a screening library is compared. Enrichments from the virtual-screening experiments are contrasted with those obtained with alternative 3D shape-matching and 2D similarity database-search methods.
A hybrid quantum mechanical−molecular mechanical (QM−MM) potential energy function with ab initio
and density functional capabilities has been implemented in the CHARMM program. It makes use of the
quantum mechanical program CADPAC and the CHARMM molecular mechanics energy function; a
GAMESS(US) interface to the CHARMM program was already available. To test the methodology, a series
of relatively small systems are studied and comparisons are made of full QM calculations with those from
various QM−MM partitions. Both density functional and Hartree−Fock calculations for the quantum region
are presented and, where possible, compared with results from previous AM1−MM calculations. For the
density functional based QM−MM calculations, the LDA and BLYP functionals were used. The performances
of both the density functional and Hartree−Fock based QM−MM calculations compare well with pure quantum
calculations. The link atom method was tested by performing a number of QM−MM simulations on the
complexes of metal cations with model ligands of biological interest. It was found that it gave good results
for the structures, binding energies, and charge distributions.
Self-organizing molecular field analysis (SOMFA) is a novel technique for three-dimensional quantitative structure-activity relations (3D-QSAR). It is simple and intuitive in concept and avoids the complex statistical tools and variable selection procedures favored by other methods. Our calculations show the method to be as predictive as the best 3D-QSAR methods available. Importantly, steric and electrostatic maps can be produced to aid the molecular design process by highlighting important molecular features. The simplicity of the technique leaves scope for further development, particularly with regard to handling molecular alignment and conformation selection. Here, the method has been used to predict the corticosteroid-binding globulin binding affinity of the "benchmark" steroids, expanded from the usual 31 compounds to 43 compounds. Test predictions have also been performed on a set of sulfonamide endothelin inhibitors.
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