Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium tuberculosis

Abstract

Dihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria, and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, they have been underexplored to combat tuberculosis, despite the essentiality of M. tuberculosis DHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. The application of a SAR by catalog strategy of an in house library for one of the identified fragments has led to a series of molecules that bind to MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that considerably differs from other DHFR antifolates, thus opening perspectives for the development of relevant MtDHFR inhibitors.

A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis

“…Although fragments often bind weakly, they tend to bind to hotspot regions of the target, forming well defined interactions that allow subsequent elaboration into larger drug-like molecules [17] , [18] . Our group and a few others have pioneered using this approach against different mycobacterial species and different protein targets with varying degrees of success [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] .…”

Identification and Evaluation of Brominated Carbazoles as a Novel Antibiotic Adjuvant Scaffold in MRSA

“… 10 , 11 The structural similarities between amoxapine and loratadine, the lead compounds identified in our previous studies, suggested that screening low-molecular-weight compounds with similar structural features could help identify novel scaffolds with similar activities for further synthetic elaboration. 12 − 14 We assembled a small library of compounds that were enriched in fused aromatic scaffolds and evaluated their ability to inhibit MRSA growth in combination with a sublethal dose of oxacillin. Several candidate scaffolds emerged from this screen.…”

“…Previously, we have disclosed the identification and study of two classes of U.S. Food and Drug Administration (FDA)-approved compounds that potentiated β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) by dampening the transcription of key resistance genes. , The structural similarities between amoxapine and loratadine, the lead compounds identified in our previous studies, suggested that screening low-molecular-weight compounds with similar structural features could help identify novel scaffolds with similar activities for further synthetic elaboration. − We assembled a small library of compounds that were enriched in fused aromatic scaffolds and evaluated their ability to inhibit MRSA growth in combination with a sublethal dose of oxacillin. Several candidate scaffolds emerged from this screen.…”

An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis

“…In 2020, an FBDD approach on DHFR was described [ 18 ]. The authors used the complex between a hit and DHFR as the starting point for further elaboration.…”