Our team will recommend compounds predicted to bind to the RNA-binding site of the SARS-CoV-2 helicase NSP13 and with potential for subsequent medicinal chemistry optimization. To this end, we will first filter a set of commercially available molecules (including those suggested in the CACHE guidelines) to reduce potential safety liabilities and undesired chemical reactivity and maximize lead-likeness. This step will also considerably reduce the chemical space that needs to be considered. The resulting dataset (approximately 18 M compounds) will be docked against a target structure suggested by the CACHE organizers using a freely available variant of Autodock Vina. Besides the Vina scoring function, the docking results will also be re-scored using RF-Score-VS v2, a state-of-the-art machine-learning scoring function, and SCORCH, an improved deep learning-based scoring function developed this year by our group. These three different scores will be combined as part of a consensus score. We will also conduct additional docking and scoring of selected compounds using more exhaustive docking settings and utilizing a “consensus docking” scheme originally proposed by our team, and which has subsequently become state-of-the art in the field (see references). We will also dock and score the library against alternative conformations of the target protein. The selection of the 100 compounds for experimental testing will be made based on the following criteria: the consensus predicted affinity scores, druglikeness scores, chemical diversity, and manual inspection of the predicted binding poses.
Autodock, PSOVina2, GWOVina, RF-Score-VS v2, SCORCH, Osiris DataWarrior, PDB2PQR, OpenBabel, RDKit
SCORCH: Improving structure-based virtual screening with machine learning classifiers, data augmentation, and uncertainty estimation. doi: 10.1016/j.jare.2022.07.001.
Comparison of ATP-binding pockets and discovery of homologous recombination inhibitors. doi: 10.1016/j.bmc.2022.116923
Consensus Docking: Improving the Reliability of Docking in a Virtual Screening Context. doi: 10.1021/ci300399w
Consensus Docking in Drug Discovery. doi: 10.2174/1573407214666181023114820