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. 2015 Aug 14;16(8):19184-94.
doi: 10.3390/ijms160819184.

Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

Alwin M Hartman  1 , Milon Mondal  2 , Nedyalka Radeva  3 , Gerhard Klebe  4 , Anna K H Hirsch  5
Affiliations

Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

Alwin M Hartman et al. Int J Mol Sci. .

Abstract

Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as malaria (plasmepsins), Alzheimer's disease (β-secretase), fungal infections (secreted aspartic proteases), and hypertension (renin). We have chosen endothiapepsin as a model enzyme of this class of enzymes, for the design, preparation and biochemical evaluation of a new series of inhibitors of endothiapepsin. Here, we have optimized a hit, identified by de novo structure-based drug design (SBDD) and DCC, by using structure-based design approaches focusing on the optimization of an amide-π interaction. Biochemical results are in agreement with SBDD. These results will provide useful insights for future structure-based optimization of inhibitors for the real drug targets as well as insights into molecular recognition.

Keywords: aspartic protease endothiapepsin; inhibitors; molecular recognition; structure-based drug design.

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Figures

Figure 1
Figure 1
(a) X-ray crystal structure of endothiapepsin co-crystallized with 1; (b) full binding mode of 1 in the active site. Color code: inhibitor skeleton: C: green, N: blue, O: red; enzyme skeleton: C: gray; water molecules: red sphere. H bonds below 3.2 Å are shown as black, dashed lines (PDB code: 4KUP) [7].
Scheme 1
Scheme 1
(a) Structures and retrosynthetic analysis of designed acylhydrazone inhibitors 2–9 starting from hit 1; (b) structures of hydrazide 10 and the aldehydes 11–18.
Figure 2
Figure 2
Structures of a series of acylhydrazone-based inhibitors 2–9.
Figure 3
Figure 3
Moloc-generated dipole moments (µ) of aromatic rings of the original hit 1 and designed acylhdrazone inhibitors 2–9.
Figure 4
Figure 4
Comparison of the binding mode of crystal structure of 1 and modeled structure of 2 in the active site of endothiapepsin. Color code: inhibitor skeleton: C: green, purple, N: blue, O: red, F: light cyan; enzyme skeleton: C: gray. H bonds below 3.2 Å are shown as black dashed lines (PDB code: 4KUP) [7].
Scheme 2
Scheme 2
Structure of (S)-2-amino-3-(1H-indol-3-yl)propanehydrazide 10.
Scheme 3
Scheme 3
General structure of acylhydrazones 2–9.
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