Hit me with your best shot: Integrated hit discovery for the next generation of drug targets.

Identification of high-quality hit chemical matter is of vital importance to the success of drug discovery campaigns. However, this goal is becoming ever harder to achieve as the targets entering the portfolios of pharmaceutical and biotechnology companies are increasingly trending towards novel and traditionally challenging to drug. This demand has fuelled the development and adoption of numerous new screening approaches, whereby the contemporary hit identification toolbox comprises a growing number of orthogonal and complementary technologies including high-throughput screening, fragment-based ligand design, affinity screening (affinity-selection mass spectrometry, differential scanning fluorimetry, DNA-encoded library screening), as well as increasingly sophisticated computational predictive approaches.

Alchemical screening of ionic crystals.

We introduce alchemical perturbations as a rapid and accurate tool to estimate fundamental structural and energetic properties in pure and mixed ionic crystals. We investigated formation energies, lattice constants, and bulk moduli for all sixteen iso-valence-electron combinations of pure pristine alkali halides involving elements Me ∈ {Na, K, Rb, Cs} and X ∈ {F, Cl, Br, I}. For rock salt, zinc-blende, and cesium chloride symmetry, alchemical Hellmann-Feynman derivatives, evaluated along lattice scans of sixteen reference crystals, have been obtained for coupling to all respective 16 × 15 target crystals.

Describing long-range charge-separation processes with subsystem density-functional theory.

Long-range charge-transfer processes in extended systems are difficult to describe with quantum chemical methods. In particular, cost-effective (non-hybrid) approximations within time-dependent density functional theory (DFT) are not applicable unless special precautions are taken. Here, we show that the efficient subsystem DFT can be employed as a constrained DFT variant to describe the energetics of long-range charge-separation processes.

Spin densities from subsystem density-functional theory: assessment and application to a photosynthetic reaction center complex model.

Subsystem density-functional theory (DFT) is a powerful and efficient alternative to Kohn-Sham DFT for large systems composed of several weakly interacting subunits. Here, we provide a systematic investigation of the spin-density distributions obtained in subsystem DFT calculations for radicals in explicit environments. This includes a small radical in a solvent shell, a π-stacked guanine-thymine radical cation, and a benchmark application to a model for the special pair radical cation, which is a dimer of bacteriochlorophyll pigments, from the photosynthetic reaction center of purple bacteria.