ACE2 is a zinc-containing metalloenzyme located on the surface of endothelial and other cells. Its discovery in 2000 led to conceptual changes in a comprehension of the renin-angiotensin system working principles. Despite the significance of ACE2, discovered during the COVID-19 pandemic, the tools to study its functions are very limited. The chemical genetics approach for the ACE2 role investigation via direct shutdown of ACE2 catalytic activity is fairly uncommon. This might be explained by the absence of the validated small molecule chemical probes for ACE2. It remains unclear, if a temporary direct shutdown of ACE2 activity, observed during COVID-19 in patients, causes damage to tissues and organs or its role is insignificant? In order to expand the chemical space of possible ACE2-probes, we started on in silico search for possible binders, using “World joined screening collection” as a compound database. Consideration of ACE2 versus ACE selectivity was a key factor determining model choice (Figure 1). In silico screening was performed using Molsoft 3.8.6/Dock 4 program packages with PyMol 2.3/VMD1.9.3 visualization. Molecular dynamics was calculated utilizing Gromacs 2019 software. Chemoinformatics part was carried out with Molsoft 3.8.6/Datawarrior 05.02/Chemaxon 5.11 program packages. As a docking result, we obtained over 10 thousand records for molecules with a notable score. We have selected one thousand molecules with the highest score, and subjected them to visual inspection in the binding site, which narrowed the list down to 150 most promising molecules-candidates. All the top-rated compounds were found to be bonded to the following sites: ARG273 – H-bond, salt bridge; TYR510 – Pi-Pi stacking; Zn-Metal coordination, salt bridge; PRO346 – H-bond; HIE505 – H-bond; HIE345 – H-bond; TYR515 – H-bond. Some of the above-noted compounds also displayed binding with sites: ALA348 – H-bond (scarce); TRP349 – Pi-Pi stacking; ARG514 – Pi-cation; HIE345 – Pi-Pi stacking; ARG273 – Pi-cation. Further in silico evaluation of ACE2 binders will be performed using alternative docking approaches and pharmacophore-based search on a similar molecular data set.

In search for selective ACE2 chemical probes: In silico studies on “world joined screening collection” compounds dataset

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.