A conformational selection method, based on hydrogen bond (Hbond) network analysis, has been designed in order to rationalize the configurations sampled using molecular dynamics (MD), which are commonly used in the estimation of the relative binding free energy of ligands to macromolecules through the MM/GBSA or MM/PBSA method. This approach makes use of protein-ligand complexes obtained from X-ray crystallographic data, as well as from molecular docking calculations. The combination of several computational approaches, like long MD simulations on protein-ligand complexes, Hbond network-based selection by scripting techniques and finally MM/GBSA, provides better statistical correlations against experimental binding data than previous similar reported studies. This approach has been successfully applied in the ranking of several protein kinase inhibitors (CDK2, Aurora A and p38), which present both diverse and related chemical structures.

We have estimated the binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition. We have employed four different methods, based on five different crystal structures: first, we docked the ligands to the proteins with induced-fit docking with the Glide software and calculated binding affinities with three energy functions. Second, the docked structures were minimised in a continuum solvent and binding affinities were calculated with the MM/GBSA method (molecular mechanics combined with generalised Born and solvent-accessible surface area solvation). Third, the docked structures were re-optimised by combined quantum mechanics and molecular mechanics (QM/MM) calculations. Then, interaction energies were calculated with quantum mechanical calculations employing 970–1160 atoms in a continuum solvent, combined with energy corrections for dispersion, zero-point energy and entropy, ligand distortion, ligand solvation, and an increase of the basis set to quadruple-zeta quality. Fourth, relative binding affinities were estimated by free-energy simulations, using the multi-state Bennett acceptance-ratio approach. Unfortunately, the results were varying and rather poor, with only one calculation giving a correlation to the experimental affinities larger than 0.7, and with no consistent difference in the quality of the predictions from the various methods. For one set of ligands, the results could be strongly improved (after experimental data were revealed) if it was recognised that one of the ligands displaced one or two water molecules. For the other two sets, the problem is probably that the ligands bind in different modes than in the crystal structures employed or that the conformation of the ligand-binding site or the whole protein changes.Electronic supplementary materialThe online version of this article (doi:10.1007/s10822-016-9942-z) contains supplementary material, which is available to authorized users.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, presenting the most devastating consequences on human health and life quality. Coumarin‐quinoline hybrids were synthesized following a very efficient and versatile strategy. Small structural variations contributed to dual acetyl/butyrylcholinesterases (AChE/BuChE) activity or selectivity towards one of these enzymes. In addition, some of the studied compounds are interesting iron chelators, presenting a tendency to be neuroprotective. Moreover, the compounds are not cytotoxic for SH‐SY5Y neuroblastoma cells. Compound 9c proved to be the most interesting compound of the studied series. This compound is selective against AChE and proved to be an excellent iron chelating agent (iron chelation at 100 μM=72.87%). Molecular docking studies were performed to establish the nature of the interaction between the studied compounds and the binding pockets, leading to a rationalization of structure–activity relationships. Compound 9c forms a well‐defined π‐stacking interaction with Phe330 and interacts with Tyr121 residue via a hydrogen bond, while the inactive compounds cannot establish these interactions. Important preliminary results against different targets, as well as some structure–activity relationships, were concluded from the experimental results.

Systematic study of the effect of fourteen chemical groups at the ortho, para and meta positions of NMA⋯halobenzene complexes showed a significant influence on halogen bonding, and also non-additive effects. A comprehensive description is reported.

A cross-docking study for describing differential binding energies of PPARγ and agonists was successful after the inclusion of protein flexibility through the use of several crystal receptor conformations.