Computational insights for predicting the binding and selectivity of peptidomimetic plasmepsin IV inhibitors against cathepsin D
Lucas Sousa Martins, Hendrik Gerhardus Kruger, Tricia Naicker, Cláudio Nahum Alves, Jerônimo Lameira, José Rogério A. Silva · RSC Advances · 2022
and are essential for the survival and growth of the parasite. Therefore, Plm enzymes are reported as an important antimalarial drug target. Herein, we have applied molecular docking, molecular dynamics (MD) simulations, and binding free energy with the Linear Interaction Energy (LIE) approach to investigate the binding of peptidomimetic PlmIV inhibitors with a particular focus on understanding their selectivity against the human Asp protease cathepsin D (CatD). The residual decomposition analysis results suggest that amino acid differences in the subsite S3 of PlmIV and CatD are responsible for the higher selectivity of the 5a inhibitor. These findings yield excellent agreement with experimental binding data and provide new details regarding van der Waals and electrostatic interactions of subsite residues as well as structural properties of the PlmIV and CatD systems.