Computationally driven discovery of SARS-CoV-2 M inhibitors: from design to experimental validation.

We report a fast-track computationally driven discovery of new SARS-CoV-2 main protease (M) inhibitors whose potency ranges from mM for the initial non-covalent ligands to sub-μM for the final covalent compound (IC = 830 ± 50 nM). The project extensively relied on high-resolution all-atom molecular dynamics simulations and absolute binding free energy calculations performed using the polarizable AMOEBA force field. The study is complemented by extensive adaptive sampling simulations that are used to rationalize the different ligand binding poses through the explicit reconstruction of the ligand-protein conformation space.

The Chemistry, Biology, and Modulation of Ammonium Nitrification in Soil.

Approximately two percent of the world's energy is consumed in the production of ammonia from hydrogen and nitrogen gas. Ammonia is used as a fertilizer ingredient for agriculture and distributed in the environment on an enormous scale to promote crop growth in intensive farming. Only 30-50 % of the nitrogen applied is assimilated by crop plants; the remaining 50-70 % goes into biological processes such as nitrification by microbial metabolism in the soil.

Defining and Exploiting Hypersensitivity Hotspots to Facilitate Abscisic Acid Agonist Optimization.

Pyrabactin resistance 1 (PYR1) and related abscisic acid (ABA) receptors are new targets for manipulating plant drought tolerance. Here, we identify and use PYR1 hypersensitive mutants to define ligand binding hotspots and show that these can guide improvements in agonist potency. One hotspot residue defined, A160, is part of a pocket that is occupied by ABA's C6 methyl or by the toluyl methyl of the synthetic agonist quinabactin (QB).

Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin.

Microtubule-targeting agents (MTAs) are some of the clinically most successful anti-cancer drugs. Unfortunately, instances of multidrug resistances to MTA have been reported, which highlights the need for developing MTAs with different mechanistic properties. One less explored class of MTAs are [1,2,4]triazolo[1,5-a]pyrimidines (TPs).