A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype A metalloprotease.
Summary (2 min read)
- 1,2 As a result, these enzymes, which are responsible for the paralysis associated with botulism, are listed as category A (highest priority) biothreat agents by the Centers for Disease Control and Prevention (CDC).
- 2-6 Furthermore, as BoNTs are now used to treat a range of medical conditions, and in many cosmetic applications,3,7-14 they are being produced in increasing quantities, making their misuse, accidental overdosing, and/or instances of adverse side effects15 more likely.
- The authors build on their previous work by describing how the refined pharmacophore33 was used to discover new small molecule inhibitors possessing the ACQ substructure and a separate ionizable, aliphatic amine component.
Results and Discussion
- Based on the identification ofN,N-bis(7-chloroquinolin-4yl)diamines and five antimalarial drugs (amodiaquine, chloroquine, quinacrine, quinidine, and quinine) as SMNPIs of the BoNT/A LC,31 the authors have continued to pursue the identification of new inhibitors of this structural class possessing the weakly basic ACQ substructure and an ionizable amine; both of these components have been found to be key to activity.
- Å from the centroid of the ACQ ), and (3) at least one of the new components from their expanded pharmacophore, either F33 (a positive ionizable moiety located 11.7-16.7 Å from the quinoline centroid) or G33 (a hydrophobic moiety located 8.5-12.5 Å from the quinoline centroid) .
- Compounds1-3 were initially examined for percent inhibition of the BoNT/A LC at 50µM concentrations, while4 was tested at a 20µM concentration.
- Molecular Docking of SMNPIs 1-4 Demonstrates a Consistency with Previous Inhibitor Binding Modes, Reinforcing The authors Structure-Based Pharmacophore Approach.
- Substituents of1-3 and one of the ACQs of4 engage in favorable hydrophobic contacts with residues Phe 162, Phe 163, and Thr 219 of hydrophobic binding subsite 131-33 (also described as the S1′ binding site34).
Component E Dominates Potency for This Structural Class.
- The final analyses of this study involved determining the importance of the structural components of1-4 to BoNT/A LC inhibition.
- To determine if incorporating pharmacophore component E might transform8 into an inhibitor, the 3R-acetyloxy group of this molecule was replaced with an ionizable 3R-NH2 substituent , effectively creating a substructure of SMNPI3 (Scheme 1), the most potent molecule of the ACQ-cholate acetate congener series (Table 1).
- Finally, to determine if it would be possible to restore the inhibitory potency of10, the 3R-O-cholate-acetate and ACQ components were tethered with an extended linker incorporating a central, secondary amine.
- Specifically, the extended linker forces the cholate-acetate portion of11 to adopt a shallower binding mode, with its C23 methoxycarbonyl oriented outside of the substrate binding cleft .
- Amino ether11 (43% from 14) was obtained in a reductive amination reaction between 6 and aldehyde15 (Scheme 1).
- An expanded/refined pharmacophore for BoNT/A LC inhibition33 was used to identify four new, potent SMNPIs of the ACQ structural class.
- This provides additional support that molecular scaffolds, which are larger than many reported BoNT/A LC inhibitors,31,40-42 are needed to provide superior inhibition.
- Finally, examination of substructures composing1-4 (i.e., compounds5-9), as well as derivatives 10 and 11, revealed the critical importance of positive-ionizable pharmacophore component E to the potencies of inhibitors in the structural class.
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...For classic inhibition, data values using a candidate inhibitor of botulinum neurotoxin type A (17) are used as inputs: E, S, Km and IC50 (in micromolar units) 0....