Physico-Chemical Insights into the Catalytic Inhibition of Plasmodium falciparum Plasmepsin II Activity by Repurposing Fluoroquinolone Drugs
Abstract
Understanding the molecular basis of enzyme inhibition is crucial for rational drug design, particularly against parasitic targets such as Plasmodium falciparum plasmepsin II (PlmII), an aspartic protease essential for hemoglobin degradation. In this study, we repurposed fluoroquinolone drugs, namely, ofloxacin, levofloxacin, and moxifloxacin, to inhibit the catalytic activity of mature PlmII (mPlmII). Thermodynamic analyses revealed favorable enthalpic and entropic contributions that correlate with the binding strength of each drug to mPlmII. Detailed enzyme kinetics assays, combined with molecular docking studies, demonstrated that moxifloxacin, with an IC50 value of 0.15 ± 0.02 μM, exhibits the most potent inhibition, primarily through hydrogen bonding with the catalytic dyad, Asp34 and Asp214. Quantum mechanics/molecular mechanics (QM/MM) (ONIOM) calculations using B3LYP/6-31G*: UFF further corroborated this binding mode, with donor-acceptor distances ranging from 2.8 to 3.3 Å, consistent with moderate to strong hydrogen bonding. Notably, methylation of the NH group disrupts these critical interactions, altering the ligand's positioning within the active site and resulting in weakened hydrogen bonds and reduced inhibitory efficacy. Overall, our findings reveal that precise hydrogen bonding with Asp34 and Asp214 is essential for the effective inhibition of mPlmII activity, and even minimal structural modifications, such as NH methylation, can impair active site engagement.
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