Capturing structure-activity relationships from chemogenomic spaces

Modeling off-target effects is one major goal of chemical biology, particularly in its applications to drug discovery. Here, we describe a new approach that allows the extraction of structure-activity relationships from large chemogenomic spaces starting from a single chemical structure. Several public source databases, offering a vast amount of data on structure and activity for a large number of different targets, have been investigated for their usefulness in automated structure-activity relationships (SAR) extraction. SAR tables were constructed by assembling similar structures around each query structure that have an activity record for a particular target. Quantitative series enrichment analysis (QSEA) was applied to these SAR tables to identify trends and to transform these trends into topomer CoMFA models. Overall more than 1700 SAR tables with topomer CoMFA models have been obtained from the ChEMBL, PubChem, and ChemBank databases. These models were able to highlight the structural trends associated with various off-target effects of marketed drugs, including cases where other structural similarity metrics would not have detected an off-target effect. These results indicate the usefulness of the QSEA approach, particularly whenever applicable with public databases, in providing a new means, beyond a simple similarity between ligand structures, to capture SAR trends and thereby contribute to success in drug discovery.     

Atomic-scale surface science phenomena studied by scanning tunneling microscopy

Following the development of the scanning tunneling microscope (STM), the technique has become a very powerful and important tool for the field of surface science, since it provides direct real-space imaging of single atoms, molecules and adsorbate structures on surfaces. From a fundamental perspective, the STM has changed many basic conceptions about surfaces, and paved the way for a markedly better understanding of atomic-scale phenomena on surfaces, in particular in elucidating the importance of local bonding geometries, defects and resolving non-periodic structures and complex co-existing phases. The so-called “surface science approach”, where a complex system is reduced to its basic components and studied under well-controlled conditions, has been used successfully in combination with STM to study various fundamental phenomena relevant to the properties of surfaces in technological applications such as heterogeneous catalysis, tribology, sensors or medical implants. In this tribute edition to Gerhard Ertl, we highlight a few examples from the STM group at the University of Aarhus, where STM studies have revealed the unique role of surface defects for the stability and dispersion of Au nanoclusters on TiO₂, the nature of the catalytically active edge sites on MoS₂ nanoclusters and the catalytic properties of Au/Ni or Ag/Ni surfaces. Finally, we briefly review how reaction between complex organic molecules can be used to device new methods for self-organisation of molecular surface structures joined by comparatively strong covalent bonds.     

Determination of accurate semiexperimental equilibrium structure of proline using efficient transformations of anharmonic force fields among the series of isotopologues

The complete semiexperimental (SE) equilibrium structure of proline (45 degrees of freedom) is determined using the mixed estimation method. The cubic force fields for the parent and eight isotopologues of proline molecule are evaluated at the MP2-FC/cc-pVTZ level in Cartesian coordinates. The accuracy of the SE structure is verified by optimising the structure with the CCSD(T) model and a basis set of quadruple-ζ quality. A significantly more accurate equilibrium structure of proline is obtained when compared to the previous one. It is shown that the employed technique is efficient for the determination of SE equilibrium structures of rather large molecules. A simple transformation of anharmonic force fields between normal coordinate and Cartesian coordinate representations is proposed. The suggested technique allows efficient evaluation of the rotation–vibration interaction constants for a number of isotopologues, once the cubic force field of any species is found either in normal or Cartesian coordinates.