Structural Characterization of Inhibitors with Selectivity against Members of a Homologous Enzyme Family

Pavlovsky, A.G.; Liu, Xuying; Faehnle, C.R.; Potente, Nina; Viola, Ronald E.

doi:10.1111/j.1747-0285.2011.01267.x

Cited by 24 publications

(29 citation statements)

References 24 publications

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“…For internal validation, the top docking score pose of the known inhibitor 2-aminoadipate (2-aa) was superimposed over the X-ray coordinates of the experimentally derived structure of this inhibitor bound to sp ASADH. 18 The docking pose of 2-aa is oriented similarly to the electron density of this bound inhibitor (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…3) were chosen from a group of inhibitors with known binding affinities for the ASADHs from both Vibrio cholerae and Streptococcus pneumoniae . 18 Correlations between measured binding affinities and the predicted affinities for each compound were assessed for various docked models. A comparative analysis of the experimental and predicted activities was performed to establish the predictive capability of this approach.…”

Section: Resultsmentioning

confidence: 99%

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Molecular docking and enzymatic evaluation to identify selective inhibitors of aspartate semialdehyde dehydrogenase

Luniwal¹,

Wang²,

Pavlovsky³

et al. 2012

Bioorganic & Medicinal Chemistry

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Microbes that have gained resistance against antibiotics pose a major emerging threat to human health. New targets must be identified that will guide the development of new classes of antibiotics. The selective inhibition of key microbial enzymes that are responsible for the biosynthesis of essential metabolites can be an effective way to counter this growing threat. Aspartate semialdehyde dehydrogenases (ASADHs) produce an early branch point metabolite in a microbial biosynthetic pathway for essential amino acids and for quorum sensing molecules. In this study, molecular modeling and docking studies were performed to achieve two key objectives that are important for the identification of new selective inhibitors of ASADH. First, virtual screening of a small library of compounds was used to identify new core structures that could serve as potential inhibitors of the ASADHs. Compounds have been identified from diverse chemical classes that are predicted to bind to ASADH with high affinity. Next, molecular docking studies were used to prioritize analogs within each class for synthesis and testing against representative bacterial forms of ASADH from Streptococcus pneumoniae and Vibrio cholerae. These studies have led to new micromolar inhibitors of ASADH, demonstrating the utility of this molecular modeling and docking approach for the identification of new classes of potential enzyme inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Molecular docking and enzymatic evaluation to identify selective inhibitors of aspartate semialdehyde dehydrogenase

Luniwal¹,

Wang²,

Pavlovsky³

et al. 2012

Bioorganic & Medicinal Chemistry

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show abstract

“…The crystal structure of aspartate beta semialdehyde dehydrogenase (ASADH) with cysteamine bound covalently to Cys128 (PDB code 3Q1L) from Streptococcus pneumonia demonstrates that cysteamine indeed can form a disulfide with a cysteine residue. In this particular example, cysteamine acted as an inhibitor of the enzyme, by blocking the thiol group of Cys128 (Pavlovsky et al 2012). The incorporation of the aminothiol cysteamine to the Cys128 had no effect on the conformation of the protein, except for the formation of an expanded network of possible hydrogen bonds in its vicinity.…”

Section: Caveatsmentioning

confidence: 99%

Cysteamine revisited: repair of arginine to cysteine mutations

Gallego

Hannibal

Häberle

et al. 2017

J of Inher Metab Disea

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Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides “proof of principle” that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since Arg to Cys changes comprise in general about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.

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“…For internal validation, the top docking score pose of the known inhibitor 2-aminoadipate (2-aa) was superimposed over the X-ray coordinates of the experimentally derived structure of this inhibitor bound to spASADH. 18 The docking pose of 2-aa is oriented similarly to the electron density of this bound inhibitor (Fig. 2).…”

Section: Molecular Modeling and Docking Studiesmentioning

confidence: 99%

“…4B). 2.1.1. Library selection-Based on our detailed understanding of the architecture of the ASADH active site and the availability of high resolution structural data for several inhibitors bound to spASADH, 18 an intuitive search for available inhibitor mimic structures was conducted using SciFinder. Beginning with a large library of potential compounds, we were able to significantly narrow the search by using our current detailed understanding of the enzyme and several selection criteria as filters.…”

Section: Molecular Modeling and Docking Studiesmentioning

confidence: 99%

1 Molecular Docking and Enzymatic Evaluation to Identify Selective Inhibitors of Aspartate Semialdehyde Dehydrogenase

Luniwal¹

2018

Preprint

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Microbes that have gained resistance against antibiotics pose a major emerging threat to human health. New targets must be identified that will guide the development of new classes of antibiotics. The selective inhibition of key microbial enzymes that are responsible for the biosynthesis of essential metabolites can be an effective way to counter this growing threat. Aspartate semialdehyde dehydrogenases (ASADHs) produce an early branch point metabolite in a microbial biosynthetic pathway for essential amino acids and for quorum sensing molecules. In this study, molecular modeling and docking studies were performed to achieve two key objectives that are important for the identification of new selective inhibitors of ASADH. First, virtual screening of a small library of compounds was used to identify new core structures that could serve as potential inhibitors of the ASADHs. Compounds have been identified from diverse chemical classes that are predicted to bind to ASADH with high affinity. Next, molecular docking studies were used to prioritize analogs within each class for synthesis and testing against representative bacterial forms of ASADH from Streptococcus pneumoniae and Vibrio cholerae.These studies have led to new micromolar inhibitors of ASADH, demonstrating the utility of this molecular modeling and docking approach for the identification of new classes of potential enzyme inhibitors.

show abstract

Structural Characterization of Inhibitors with Selectivity against Members of a Homologous Enzyme Family

Cited by 24 publications

References 24 publications

Molecular docking and enzymatic evaluation to identify selective inhibitors of aspartate semialdehyde dehydrogenase

Molecular docking and enzymatic evaluation to identify selective inhibitors of aspartate semialdehyde dehydrogenase

Cysteamine revisited: repair of arginine to cysteine mutations

1 Molecular Docking and Enzymatic Evaluation to Identify Selective Inhibitors of Aspartate Semialdehyde Dehydrogenase

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