Challenges in the determination of the binding modes of non-standard ligands in X-ray crystal complexes

Despite its central role in structure based drug design the determination of the binding mode (position, orientation and conformation in addition to protonation and tautomeric states) of small heteromolecular ligands in protein:ligand complexes based on medium resolution X-ray diffraction data is highly challenging. In this perspective we demonstrate how a combination of molecular dynamics simulations and free energy (FE) calculations can be used to correct and identify thermodynamically stable binding modes of ligands in X-ray crystal complexes. The consequences of inappropriate ligand structure, force field and the absence of electrostatics during X-ray refinement are highlighted. The implications of such uncertainties and errors for the validation of virtual screening and fragment-based drug design based on high throughput X-ray crystallography are discussed with possible solutions and guidelines. © Springe

Solid State Chemistry of Clathrate Phases: Crystal Structure, Chemical Bonding and Preparation Routes

Clathrates represent a family of inorganic materials called cage compounds. The key feature of their crystal structures is a three-dimensional (host) framework bearing large cavities (cages) with 20-28 vertices. These polyhedral cages bear-as a rule-guest species. Depending on the formal charge of the framework, clathrates are grouped in anionic, cationic and neutral. While the bonding in the framework is of (polar) covalent nature, the guest-host interaction can be ionic, covalent or even van-der Waals, depending on the chemical composition of the clathrates. The chemical composition and structural features of the cationic clathrates can be described by the enhanced Zintl concept, whereas the composition of the anionic clathrates deviates often from the Zintl counts, indicating additional atomic interactions in comparison with the ionic-covalent Zintl model. These interactions can be visualized and studied by applying modern quantum chemical approaches such as electron localizability

Advancement of Structure-Activity Relationship of Multidrug Resistance-Associated Protein 2 Interactions

Multidrug resistance-associated protein 2 (MRP2/ABCC2) is mainly expressed in the apical phase of barrier membranes. It functions as a critical efflux pump in the biliary excretion of endogenous substances, such as conjugated bilirubin and bile salts, as well as many structurally diverse xenobiotics and their metabolites. Due to its important role in defining ADME/Tox properties, efforts have emerged to build the structure–activity relationship (SAR) for MRP2/ABCC2 at early stages of drug discovery process. MRP2/ABCC2 is a member of the integral membrane protein family whose high-resolution crystal structure has not been described. To overcome the obstacle of lacking detailed structural depiction, various molecular modeling approaches have been applied to derive the structural requirements for binding interactions with MRP2/ABCC2 protein, including two-dimensional (2D) and three-dimensional (3D) quantitative SAR (QSAR) analysis, pharmacophore models, and homology modeling of the transporter. Here we summarize recent progresses in understanding the SAR of MRP2/ABCC2 recognition of substrates and/or inhibitors, and describe some of the useful in vitro tools for characterizing the interactions with the transporter