Fragment-Based Drug Discovery against Mycobacteria: The Success and Challenges

Abstract

The emergence of drug-resistant mycobacteria, including Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria (NTM), poses an increasing global threat that urgently demands the development of new potent anti-mycobacterial drugs. One of the approaches toward the identification of new drugs is fragment-based drug discovery (FBDD), which is the most ingenious among other drug discovery models, such as structure-based drug design (SBDD) and high-throughput screening. Specialized techniques, such as X-ray crystallography, nuclear magnetic resonance spectroscopy, and many others, are part of the drug discovery approach to combat the Mtb and NTM global menaces. Moreover, the primary drawbacks of traditional methods, such as the limited measurement of biomolecular toxicity and uncertain bioavailability evaluation, are successfully overcome by the FBDD approach. The current review focuses on the recognition of fragment-based drug discovery as a popular approach using virtual, computational, and biophysical methods to identify potent fragment molecules. FBDD focuses on designing optimal inhibitors against potential therapeutic targets of NTM and Mtb (PurC, ArgB, MmpL3, and TrmD). Additionally, we have elaborated on the challenges associated with the FBDD approach in the identification and development of novel compounds. Insights into the applications and overcoming the challenges of FBDD approaches will aid in the identification of potential therapeutic compounds to treat drug-sensitive and drug-resistant NTMs and Mtb infections.

Advances in computational frameworks in the fight against TB: The way forward

“…For example, Thiolactomycin and Pantetheine analogs have been identified to bind with KasA with promising binding affinities. DprE1 inhibitors as derived through FBDD are at the early stages of clinical evaluation (Mallakuntla et al, 2022;Togre et al, 2022). The complex pathology of Mtb which involves multiple molecular agents (involved in pathogen entry and sustenance) and the failure of multiple innate immune mediators highlight the need for the adoption of a multi-target approach.…”

“…For example, Thiolactomycin and Pantetheine analogs have been identified to bind with KasA with promising binding affinities. DprE1 inhibitors as derived through FBDD are at the early stages of clinical evaluation ( Mallakuntla et al, 2022 ; Togre et al, 2022 ).…”

Advances of the Target-Based and Phenotypic Screenings and Strategies in Drug Discovery

“…The fragment-based drug design (FBDD) is one particularly suitable application for biophysical methods. The methods commonly used in FBDD are nuclear magnetic resonance (NMR), surface plasmon resonance, and X-ray crystallography [6,8].…”

Fragment-based drug discovery for disorders of the central nervous system: designing better drugs piece by piece

“…Commonly, these techniques are used in tandem to verify the validity of a fragment hit. These screening methods have been reviewed in detail ( Kirsch et al, 2019 ; Li, 2020 ; Togre et al, 2022 ); this section therefore serves as a brief summary of techniques that have been prominent in recent CNS drug discovery programs highlighted in this review.…”