Pyrrolidine Derivatives as Plasmepsin Inhibitors: Binding Mode Analysis Assisted by Molecular Dynamics Simulations of a Highly Flexible Protein

摘要

Plasmepsins II (EC number: 3.4.23.39) and IV (EC number: 3.4.23.B14) are aspartic proteases present in the food vacuole of the malaria parasite Plasmodium falciparum and are involved in host hemoglobin degradation. A series of pyrrolidine derivatives, originally synthesized as HIV-1 protease inhibitors, were tested for activity against plasmepsin (Plm). Inhibitors in the nanomolar range were discovered for the Plm II and IV iso-forms. Detailed studies were carried out to identify putative binding modes that help to explain the underlying structure-activity relationships. Reasonable binding modes were generat-ed for pyrrolidine-3,4-diester derivatives and a substituted 3,4-diaminopyrrolidine inhibitor by using a crystal structure of inhibitor-bound Plm II (PDB ID: 1LEE). Modeling studies indicated that the flap of available Plm crystal structures is not sufficiently opened to accommodate the 3,4-bis(aminomethylene)pyrro-lidines. Molecular dynamics simulations were performed to analyze the flexibility of the protein in greater detail, leading to a binding mode hypothesis for the 3,4-bis(aminomethylene)pyr-rolidines and providing further insight and general implications for the design of Plm II inhibitors.