De Novo Fragment Design for Drug Discovery and Chemical Biology

Automated molecular de novo design led to the discovery of an innovative inhibitor of death‐associated protein kinase 3 (DAPK3). An unprecedented crystal structure of the inactive DAPK3 homodimer shows the fragment‐like hit bound to the ATP pocket. Target prediction software based on machine learning models correctly identified additional macromolecular targets of the computationally designed compound and the structurally related marketed drug azosemide. The study validates computational de novo design as a prime method for generating chemical probes and starting points for drug discovery.     

The proton nuclear magnetic shielding tensors in biphenyl: experiment and theory

Line-narrowing multiple pulse techniques are applied to a spherical sample crystal of biphenyl. The 10 different proton shielding tensors in this compound are determined. The accuracy level for the tensor components is 0.3 ppm. The assignment of the measured tensors to the corresponding proton sites is given careful attention. Intermolecular shielding contributions are calculated by the induced magnetic point dipole model with empirical atom and bond susceptibilities (distant neighbours) and by a new quantum chemical method (near neighbours). Subtracting the intermolecular contributions from the (correctly assigned) measured shielding tensors leads to isolated-molecule shielding tensors for which there are symmetry relations. Compliance to these relations is the criterion for the correct assignment. The success of this program indicates that intermolecular proton shielding contributions can be calculated to better than 0.5 ppm. The isolated-molecule shielding tensors obtained from experiment and calculated intermolecular contributions are compared with isolated-molecule quantum chemical results. Expressed in the icosahedral tensor representation, the rms differences of the respective tensor components are below 0.5 ppm for all proton sites in biphenyl. In the isolated molecule, the least shielded direction of all protons is the perpendicular to the molecular plane. For the para proton, the intermediate principal direction is along the C-H bond. It is argued that these relations also hold for the protons in the isolated benzene molecule.     

The ground state of propynal

The millimeter wave spectrum of propynal, HCCCHO, has been studied in the ground vibrational state. A detailed centrifugal distortion analysis has been carried out on the combined data of newly assigned millimeter wave rotational transitions (up to 200 GHz) together with the microwave transitions reported earlier. A total of 90 transitions as high as J = 20 and K = 12 could be fitted with a standard deviation of 87 kHz. This analysis yielded a complete set of ground state rotational and centrifugal distortion constants. The rotational constants are in MHz:

$\text{A = 68 035.2994 ± 0.0429,}$

$\text{B =}\text{4826.3014 ± 0.0073,}$

$\text{C =}\text{4499.5107 ± 0.0069.}$

     

“Scaffold-Hopping” by Topological Pharmacophore Search: A Contribution to Virtual Screening

A chemically advanced template search (CATS) based on topological pharmacophore models has been developed as a technique for virtual screening. This technique has successfully identified novel potent Ca²⁺ antagonists (such as 2 ) that have a similar activity to 1 (a known T-channel blocking agent) in a library of several hundred thousand compounds on the basis of a correlation vector representation.