Identification of M. tuberculosis Thioredoxin Reductase Inhibitors Based on High-Throughput Docking Using Constraints

Abstract

A virtual screening campaign is presented that led to small molecule inhibitors of thioredoxin reductase of Mycobacterium tuberculosis (MtTrxR) that target the protein-protein interaction site for the substrate thioredoxin (Trx). MtTrxR is a promising drug target because it dominates the Trx-dependent hydroperoxide metabolism and the reduction of ribonucleotides, thus facilitating survival and proliferation of M. tuberculosis. Moreover, MtTrxR sufficiently differs from its human homologs to suggest the possibility of selective inhibition if the MtTrxR-Trx interaction site is targeted. To this end, high-throughput docking of 6.5 million virtual compounds to the thioredoxin binding site of MtTrxR combined with constraints as filtering steps was applied. A total of 170 high-scoring compounds yielded 18 compounds that inhibited MtTrxR with IC50 values up to the low micromolar range, thus revealing that the protein-protein interaction site of MtTrxR is indeed druggable. Most importantly, selectivity toward MtTrxR in comparison to human TrxR (HsTrxR) is also demonstrated.

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

“…[161][162][163] Figure 6. b-Sheet mimetics: Turn mimetics: l-Pro-d-Pro (6), dibenzofuran derivatives (7), oligourea (8), azobenzene (9); Macrocyclization: head to tail (10), side chain to side chain cross-link with a disulfide (11) and 1,2,3-triazole ring (12), side chain to side chain p-p interaction (Trp-Trp; 13) and cation-p interaction (N d -trimethylornithine-Trp; 14); b-strand-enforcing amino acids: 1,6-dihydro-3(2H)-pyridinone (Ach, 15), Hao building block (16), diphenylacetylene building block (17); Structural mimetics: piperidine-piperidinone-based strand mimetic (18); class A/B: yellow; class C: blue. Box: structure used in the context of PPI inhibition.…”

“…[1] Additionally, computational tools have been used to design more diverse sets of compounds or to perform in silico screens with improved virtual libraries. [10][11][12] In a structure-based approach, peptide binding epitopes derived from protein interaction sites can serve as a starting point for the design of PPI inhibitors. Such epitopes are defined by the secondary structure of the underlying polypeptide chain that aligns amino acid side chains in a defined manner.…”

“…This stimulated the search for alternative strategies involving fragment‐based screens or natural product inspired libraries that contain molecules with relatively high molecular weights and a large number of stereocenters 1. Additionally, computational tools have been used to design more diverse sets of compounds or to perform in silico screens with improved virtual libraries 10–12. In a structure‐based approach, peptide binding epitopes derived from protein interaction sites can serve as a starting point for the design of PPI inhibitors.…”

Improved understanding of pathogenesis from protein interactions inMycobacteriumtuberculosis

“…Koch et al used docking methods to screen small molecule inhibitors of Trx reductase in M. tuberculosis (MtTrxR) that target the protein-protein interaction site for the substrate Trx [95]. Compared with experimentalbased methods, computational methods usually require information such as 3D structure and interaction interface.…”

Strukturbasierte Entwicklung von Protein‐Protein‐Interaktionsinhibitoren: Stabilisierung und Nachahmung von Peptidliganden

“…Diese Tatsache hat die Suche nach alternativen Strategien angeregt, die unter anderem fragmentbasierte Screens oder naturstoffinspirierte Bibliotheken umfassen 1. Darüber hinaus werden computergestützte Hilfsmittel genutzt, um strukturell diversere Bibliotheken zu generieren oder um computergestützte Screens mit verbesserten virtuellen Bibliotheken durchzuführen 10–12. In einem strukturbasierten Ansatz werden Peptidliganden, die von Proteininteraktionsflächen abgeleitet werden, als Startpunkt für die Entwicklung von PPI‐Inhibitoren verwendet.…”