Parallelized Tools for the Preparation and Curation of Large Libraries for Virtual Screening.

We introduce a software package, ParaLig, that provides solutions for several workflows occurring repeatedly in computational drug discovery: parameterization of small molecules with partial charges and free energies of solvation, generation of conformers, virtual chemical reactions, creating combinatorial libraries, and molecule editing tasks. Throughout, we emphasize the maintenance/creation of 3D coordinates and better interoperability. The latter is achieved by stable embedding of meta-information into output files and by improving the mutual compatibility of molecular representations (e.

The physics-AI dialogue in drug design.

A long path has led from the determination of the first protein structure in 1960 to the recent breakthroughs in protein science. Protein structure prediction and design methodologies based on machine learning (ML) have been recognized with the 2024 Nobel prize in Chemistry, but they would not have been possible without previous work and the input of many domain scientists. Challenges remain in the application of ML tools for the prediction of structural ensembles and their usage within the software pipelines for structure determination by crystallography or cryogenic electron microscopy.

Small-Molecule Inhibitors of the m7G-RNA Writer METTL1.

We discovered the first inhibitors of the m7G-RNA writer METTL1 by high-throughput docking and an enzymatic assay based on luminescence. Eleven compounds, which belong to three different chemotypes, show inhibitory activity in the range 40-300 μM. Two adenine derivatives identified by docking have very favorable ligand efficiency of 0.

The catalytic mechanism of the RNA methyltransferase METTL3.

The complex of methyltransferase-like proteins 3 and 14 (METTL3-14) is the major enzyme that deposits N-methyladenosine (mA) modifications on messenger RNA (mRNA) in humans. METTL3-14 plays key roles in various biological processes through its methyltransferase (MTase) activity. However, little is known about its substrate recognition and methyl transfer mechanism from its cofactor and methyl donor -adenosylmethionine (SAM).

Disrupting Dimeric β-Amyloid by Electric Fields.

The early oligomers of the amyloid Aβ peptide are implicated in Alzheimer's disease, but their transient nature complicates the characterization of their structure and toxicity. Here, we investigate the stability of the minimal toxic species, i.e.

The catalytic mechanism of the RNA methyltransferase METTL3.

The complex of methyltransferase-like proteins 3 and 14 (METTL3-14) is the major enzyme that deposits N6-methyladenosine (m6A) modifications on mRNA in humans. METTL3-14 plays key roles in various biological processes through its methyltransferase (MTase) activity. However, little is known about its substrate recognition and methyl transfer mechanism from its cofactor and methyl donor S-adenosylmethionine (SAM).

Domino Effect in Allosteric Signaling of Peptide Binding.

While being a thoroughly studied model of dynamic allostery in a small protein, the pathway of signal transduction in the PDZ3 domain has not been fully determined. Here, we investigate peptide binding to the PDZ3 domain by conventional and fully data-driven analyses of molecular dynamics simulations. First, we identify isoleucine 37 as a key residue by widely used computational procedures such as cross-correlation and community network analysis.