Identification of target-specific bioisosteric fragments from ligand-protein crystallographic data

Bioisosteres are functional groups or atoms that are structurally different but that can form similar intermolecular interactions. Potential bioisosteres were identified here from analysing the X-ray crystallographic structures for sets of different ligands complexed with a fixed protein. The protein was used to align the ligands with each other, and then pairs of ligands compared to identify substructural features with high volume overlap that occurred in approximately the same region of geometric space. The resulting pairs of substructural features can suggest potential bioisosteric replacements for use in lead-optimisation studies. Experiments with 12 sets of ligand-protein complexes from the Protein Data Bank demonstrate the effectiveness of the procedure

Permeation of small molecules through a lipid bilayer: a computer simulation study

To reach their biological target, drugs have to cross cell membranes, and understanding passive membrane permeation is therefore crucial for rational drug design. Molecular dynamics simulations offer a powerful way of studying permeation at the single molecule level, yielding detailed dynamic and thermodynamic data. Biological membranes have a very inhomogeneous character and a highly anisotropic behavior. Starting from a computer model proven to reproduce the physical properties of such a complex system, the permeation of small organic molecules across a lipid bilayer model has been studied. Free energy profiles and diffusion coefficients along the bilayer normal have been calculated for small organic molecules by means of all-atom molecular dynamics (MD) simulations constraining the compounds at chosen depths inside the membrane. These data also allow for the calculation of permeability coefficients, the results for which have been compared with experimental data. The calculated permeability coefficients are generally 1 order of magnitude larger than the equivalent experimental data, but the molecules' relative permeability coefficients are reproduced