Screening the Pathogen Box to Discover and Characterize New Cruzain and CatL Inhibitors.

Chagas disease and Human African Trypanosomiasis, caused by and , respectively, pose relevant health challenges throughout the world, placing 65 to 70 million people at risk each. Given the limited efficacy and severe side effects associated with current chemotherapy, new drugs are urgently needed for both diseases. Here, we report the screening of the Pathogen Box collection against cruzain and CatL, validated targets for Chagas disease and Human African Trypanosomiasis, respectively.

Experimental and Computational Study of Aryl-thiosemicarbazones Inhibiting Cruzain Reveals Reversible Inhibition and a Stepwise Mechanism.

is a parasite that infects about 6-7 million people worldwide, mostly in Latin America, causing Chagas disease. Cruzain, the main cysteine protease of , is a validated target for developing drug candidates for Chagas disease. Thiosemicarbazones are one of the most relevant warheads used in covalent inhibitors targeting cruzain.

Bespoke library docking for 5-HT receptor agonists with antidepressant activity.

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors.

Synthesis, Design, and Structure-Activity Relationship of a Benzenesulfonylpiperazine Series against Trypanosoma cruzi.

Chagas disease is a neglected tropical disease, endemic in Latin America and caused by the protozoan parasite Trypanosoma cruzi. Available treatments show low cure efficacy during the chronic phase of the disease and cause a series of side effects, reinforcing the need to develop new drugs against Chagas disease. In this work, we describe the optimization of a trypanocidal hit compound recently reported in phenotypic high-throughput screening studies against Trypanosoma cruzi.

PyAutoFEP: An Automated Free Energy Perturbation Workflow for GROMACS Integrating Enhanced Sampling Methods.

Free energy perturbation (FEP) calculations are now routinely used in drug discovery to estimate the relative FEB (RFEB) of small molecules to a biomolecular target of interest. Using enhanced sampling can improve the correlation between predictions and experimental data, especially in systems with conformational changes. Due to the large number of perturbations required in drug discovery campaigns, the manual setup of FEP calculations is no longer viable.

Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking.

The SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain.

Synthesis and biological evaluation of potential inhibitors of the cysteine proteases cruzain and rhodesain designed by molecular simplification.

Analogues of 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]indol-4-amine 1, a known cruzain inhibitor, were synthesized using a molecular simplification strategy. Five series of analogues were obtained: indole, pyrimidine, quinoline, aniline and pyrrole derivatives. The activity of the compounds was evaluated against the enzymes cruzain and rhodesain as well as against Trypanosoma cruzi amastigote and trypomastigote forms.