Synthesis, biological evaluation, hydration site thermodynamics, and chemical reactivity analysis of α-keto substituted peptidomimetics for the inhibition of Plasmodium falciparum

Estimation of Solvation Entropy and Enthalpy via Analysis of Water Oxygen–Hydrogen Correlations

“…Indeed, alternative methods are available, which appear to be useful for ligand design 10,39–41 despite their focus on analysis of solvation thermodynamics. 9–12,14–17 However, several challenges (discussed in the Introduction section) need to be addressed prior to extending such approaches to account for all contributions to the free energy, particularly concerning improvements in accuracy/efficiency without the use of empirical parametrization (which can hamper the general applicability of these techniques).…”

Design, Synthesis, and Biological Evaluation of Peptidomimetic N‐Substituted Cbz‐4‐Hyp‐Hpa‐Amides as Novel Inhibitors of Plasmodium falciparum

“…The results of synthetic, protein modeling, docking studies, and virtual screening studies [ ][ ][ ] lead to the conclusion that to obtain highly active agents, efforts should be made to the design of peptidomimetic molecules with high affinity to the binding site of the enzyme.…”

“…Recently, a series of peptidomimetic hydroxyprolyl‐homophenylalanylketones were designed, synthesized, and evaluated for inhibition of the Plasmodium falciparum cysteine proteases FP‐2 and FP‐3 . Analysis of structures mostly potent peptidomimetics 9 ( IC 50 80 n m against FP‐2 and 60 n m against FP‐3), 10 ( IC 50 1.10 μ m against FP‐2 and 0.52 μ m against FP‐3) ( Fig.…”

“…It was assumed that these peptides would be more resistant to peptidase and would have an increased half‐life. Furthermore, the design can lead to decreased analog flexibility and improved binding thermodynamics, which can even be increased by the introduction of the rigid l ‐proline residue …”

Computational Studies of the Mechanism of Catalysis and Inhibition of Cysteine Proteases

“…Several types of inhibitors of FP2 have been reported in the last years to be capable to inactive the enzyme; [195][196][197][198][199][200] however, only few structures reported in the PDB correspond to the crystal structure of FP2 with its inhibitors. 195,201,202 One of them is the structure of FP2 complexed with E64 (see Figure 5.4.1), 195 the first epoxysuccinyl peptide discovered and a natural potent and specific irreversible inhibitor of CP.…”