QSAR modeling approaches to identify a novel ACE2 inhibitor that selectively bind with the C and N terminals of the ectodomain

Due to the high rates of drug development failure and the massive expenses associated with drug discovery, repurposing existing drugs has become more popular. As a result, we have used QSAR modelling on a large and varied dataset of 657 compounds in an effort to discover both explicit and subtle structural features requisite for ACE2 inhibitory activity, with the goal of identifying novel hit molecules. The QSAR modelling yielded a statistically robust QSAR model with high predictivity (R²_tr=0.84, R²_ex=0.79), previously undisclosed features, and novel mechanistic interpretations. The developed QSAR model predicted the ACE2 inhibitory activity (_PIC₅₀) of 1615 ZINC FDA compounds. This led to the detection of a _PIC₅₀ of 8.604 M for the hit molecule (ZINC000027990463). The hit molecule’s docking score is −9.67 kcal/mol (RMSD 1.4). The hit molecule revealed 25 interactions with the residue ASP40, which defines the N and C termini of the ectodomain of ACE2. The HIT molecule conducted more than thirty contacts with water molecules and exhibited polar interaction with the ARG522 residue coupled with the second chloride ion, which is 10.4 nm away from the zinc ion. Both molecular docking and QSAR produced comparable findings. Moreover, MD simulation and MMGBSA studies verified docking analysis. The MD simulation showed that the hit molecule-ACE2 receptor complex is stable for 400 ns, suggesting that repurposed hit molecule 3 is a viable ACE2 inhibitor.