Advances and challenges in drug design against tuberculosis: application of in silico approaches

ABSTRACT

Introduction: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains the deadliest infectious disease in the world with one-third of the world’s population thought to be infected. Over the years, TB mortality rate has been largely reduced; however, this progress has been threatened by the increasing appearance of multidrug-resistant Mtb. Considerable recent efforts have been undertaken to develop new generation antituberculosis drugs. Many of these attempts have relied on in silico approaches, which have emerged recently as powerful tools complementary to biochemical attempts.

Areas covered: The authors review the status of pharmaceutical drug development against TB with a special emphasis on computational work. They focus on those studies that have been validated by in vitro and/or in vivo experiments, and thus, that can be considered as successful. The major goals of this review are to present target protein systems, to highlight how in silico efforts compliment experiments, and to aid future drug design endeavors.

Expert opinion: Despite having access to all of the gene and protein sequences of Mtb, the search for new optimal treatments against this deadly pathogen are still ongoing. Together with the geometric growth of protein structural and sequence databases, computational methods have become a powerful technique accelerating the successful identification of new ligands.

KEYWORDS:

• Tuberculosis
• computer aided drug design
• molecular docking
• scoring functions
• pharmacophore
• QSAR
• lead optimization

Article highlights

• In silico computational approaches have become a powerful tool for acceralating antituberculosis drug discovery

• The accuracy of the current structure-based methods should be improved in the future by including adequate treatment of target protein flexibility, solvation effects, and induced electronic polarization

• Advanced simulations based on free energy techniques and explicit solvent molecular dynamics should be more applied to the problems of drug design

• The screened molecules that do not possess activity against the target should be reported to facilitate the future drug design campaigns against this target

• Accurate methods for predicting drug permeability through the cell wall of Gram-positive and/or negative bacteria should be developed in future

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The authors are supported by the Agence Nationale de la Recherche (ANR-2010-EMMA-044-01, ANR-18-CE44-0002-01).