The TB Structural Genomics Consortium: Providing a Structural Foundation for Drug Discovery

Goulding, Celia W.; Apostol, Marcin I.; Anderson, D.; Gill, Harindarpal S.; Smith, Clare V.; Kuo, Mack; KukYang, Jin; Waldo, Geoffrey S.; Suh, Se Won; Chauhan, Radha; Kale, Avinash; Bachhawat, Nandita; Mande, Shekhar C.; Johnston, Jodie M.; Lott, J.S.; Baker, Edward N.; Arcus, Vickery L.; Leys, D.; McLean, Kirsty J.; Munro, Andrew W.; Berendzen, Joel; Sharma, Vivek; Park, Min; Eisenberg, David; Sacchettini, James C.; Alber, Tom; Rupp, Bernhard; Jacobs, William R.; Terwilliger, Thomas C.

doi:10.2174/1568005023342551

Cited by 65 publications

(4 citation statements)

References 64 publications

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“…These results suggest that at least two strategies are conceivable to inhibit Hma, and potentially other mycolic acid methyltransferases, which share high structural similarities [33,49]. First, elaborating from the ZT275 and ZT320 fragments would yield compounds that simultaneously interfere with substrate binding, as they occupy the substrate binding site, and prevent cofactor binding, as they induce structural modifications of the protein that are not compatible with the presence of SAM.…”

Section: Computed Binding Energies Of Fragments and Chimeric Compoundsmentioning

confidence: 99%

Fragment-Based Ligand Discovery Applied to the Mycolic Acid Methyltransferase Hma (MmaA4) from Mycobacterium tuberculosis: A Crystallographic and Molecular Modelling Study

et al. 2021

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The mycolic acid biosynthetic pathway represents a promising source of pharmacological targets in the fight against tuberculosis. In Mycobacterium tuberculosis, mycolic acids are subject to specific chemical modifications introduced by a set of eight S-adenosylmethionine dependent methyltransferases. Among these, Hma (MmaA4) is responsible for the introduction of oxygenated modifications. Crystallographic screening of a library of fragments allowed the identification of seven ligands of Hma. Two mutually exclusive binding modes were identified, depending on the conformation of residues 147–154. These residues are disordered in apo-Hma but fold upon binding of the S-adenosylmethionine (SAM) cofactor as well as of analogues, resulting in the formation of the short η1-helix. One of the observed conformations would be incompatible with the presence of the cofactor, suggesting that allosteric inhibitors could be designed against Hma. Chimeric compounds were designed by fusing some of the bound fragments, and the relative binding affinities of initial fragments and evolved compounds were investigated using molecular dynamics simulation and generalised Born and Poisson–Boltzmann calculations coupled to the surface area continuum solvation method. Molecular dynamics simulations were also performed on apo-Hma to assess the structural plasticity of the unliganded protein. Our results indicate a significant improvement in the binding properties of the designed compounds, suggesting that they could be further optimised to inhibit Hma activity.

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Section: Computed Binding Energies Of Fragments and Chimeric Compoundsmentioning

confidence: 99%

Fragment-Based Ligand Discovery Applied to the Mycolic Acid Methyltransferase Hma (MmaA4) from Mycobacterium tuberculosis: A Crystallographic and Molecular Modelling Study

et al. 2021

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“…The Consortium, comprising 460 members from 93 research centers spanning 15 countries, employs state-of-the-art technologies for gene cloning, protein expression and structure determination. Since the inception of the TBSGC in 2000, approximately 250 Mtb protein structures have been elucidated by Consortium members, accounting for over one-third of Mtb structures deposited into the Protein Data Bank (PDB, http://www.rcsb.org), many of which have been previously reviewed 1-4 . The wealth of information from atomic resolution details of proteins, particularly in complex with their cognate substrates or cofactors as well as protein-protein interaction networks, may aid other scientists in interpreting their genetic and biochemical data and may ultimately be exploited in rational structure-based design of therapeutics for TB.…”

Section: Introductionmentioning

confidence: 99%

The TB Structural Genomics Consortium: A decade of progress

et al. 2011

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Summary The TB Structural Genomics Consortium is a worldwide organization of collaborators whose mission is the comprehensive structural determination and analyses of Mycobacterium tuberculosis proteins to ultimately aid in tuberculosis diagnosis and treatment. Congruent to the overall vision, Consortium members have additionally established an integrated facilities core to streamline M. tuberculosis structural biology and developed bioinformatics resources for data mining. This review aims to share the latest Consortium developments with the TB community, including recent structures of proteins that play significant roles within M. tuberculosis. Atomic resolution details may unravel mechanistic insights and reveal unique and novel protein features, as well as important protein-protein and protein-ligand interactions, which ultimately leads to a better understanding of M. tuberculosis biology and may be exploited for rational, structure-based therapeutics design.

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“…The TB-drugome is publically available (http://funsite.sdsc.edu/drugome/TB) and has the potential to be a valuable resource for the development of safe and efficient anti-tubercular drugs. Structural biology and structural genomics efforts continue to increase the structural coverage of the M.tb proteome [ 19 ]–[ 21 ], as well as those of other pathogens. This will improve the robustness of the TB-drugome and facilitate the application of this methodology to other pathogens.…”

Section: Introductionmentioning

confidence: 99%

The Mycobacterium tuberculosis Drugome and Its Polypharmacological Implications

et al. 2010

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We report a computational approach that integrates structural bioinformatics, molecular modelling and systems biology to construct a drug-target network on a structural proteome-wide scale. The approach has been applied to the genome of Mycobacterium tuberculosis (M.tb), the causative agent of one of today's most widely spread infectious diseases. The resulting drug-target interaction network for all structurally characterized approved drugs bound to putative M.tb receptors, we refer to as the ‘TB-drugome’. The TB-drugome reveals that approximately one-third of the drugs examined have the potential to be repositioned to treat tuberculosis and that many currently unexploited M.tb receptors may be chemically druggable and could serve as novel anti-tubercular targets. Furthermore, a detailed analysis of the TB-drugome has shed new light on the controversial issues surrounding drug-target networks [1]–[3]. Indeed, our results support the idea that drug-target networks are inherently modular, and further that any observed randomness is mainly caused by biased target coverage. The TB-drugome (http://funsite.sdsc.edu/drugome/TB) has the potential to be a valuable resource in the development of safe and efficient anti-tubercular drugs. More generally the methodology may be applied to other pathogens of interest with results improving as more of their structural proteomes are determined through the continued efforts of structural biology/genomics.

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The TB Structural Genomics Consortium: Providing a Structural Foundation for Drug Discovery

Cited by 65 publications

References 64 publications

Fragment-Based Ligand Discovery Applied to the Mycolic Acid Methyltransferase Hma (MmaA4) from Mycobacterium tuberculosis: A Crystallographic and Molecular Modelling Study

Fragment-Based Ligand Discovery Applied to the Mycolic Acid Methyltransferase Hma (MmaA4) from Mycobacterium tuberculosis: A Crystallographic and Molecular Modelling Study

The TB Structural Genomics Consortium: A decade of progress

The Mycobacterium tuberculosis Drugome and Its Polypharmacological Implications

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