A structural and energetic model for the slow-onset inhibition of the mycobacterium tuberculosis ENoyl-ACP reductase InhA

Huei Jiun Li, Cheng Tsung Lai, Pan Pan, Weixuan Yu, Nina Liu, Gopal R. Bommineni, Miguel Garcia-Diaz, Carlos Simmerling, Peter J. Tonge

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Slow-onset enzyme inhibitors are of great interest for drug discovery programs since the slow dissociation of the inhibitor from the drug-target complex results in sustained target occupancy leading to improved pharmacodynamics. However, the structural basis for slow-onset inhibition is often not fully understood, hindering the development of structure-kinetic relationships and the rational optimization of drug-target residence time. Previously we demonstrated that slow-onset inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA correlated with motions of a substrate-binding loop (SBL) near the active site. In the present work, X-ray crystallography and molecular dynamics simulations have been used to map the structural and energetic changes of the SBL that occur upon enzyme inhibition. Helix-6 within the SBL adopts an open conformation when the inhibitor structure or binding kinetics is substrate-like. In contrast, slow-onset inhibition results in large-scale local refolding in which helix-6 adopts a closed conformation not normally populated during substrate turnover. The open and closed conformations of helix-6 are hypothesized to represent the EI and EI* states on the two-step induced-fit reaction coordinate for enzyme inhibition. These two states were used as the end points for nudged elastic band molecular dynamics simulations resulting in two-dimensional potential energy profiles that reveal the barrier between EI and EI, thus rationalizing the binding kinetics observed with different inhibitors. Our findings indicate that the structural basis for slow-onset kinetics can be understood once the structures of both EI and EI* have been identified, thus providing a starting point for the rational control of enzyme-inhibitor binding kinetics.

Original languageEnglish (US)
Pages (from-to)986-993
Number of pages8
JournalACS Chemical Biology
Volume9
Issue number4
DOIs
StatePublished - Apr 18 2014
Externally publishedYes

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Structural Models
Mycobacterium tuberculosis
Oxidoreductases
Kinetics
Substrates
Enzyme inhibition
Conformations
Enzyme Inhibitors
Molecular Dynamics Simulation
Molecular dynamics
Pharmacodynamics
X ray crystallography
X Ray Crystallography
Computer simulation
Enzymes
Drug Discovery
Potential energy
Pharmaceutical Preparations
Catalytic Domain

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

A structural and energetic model for the slow-onset inhibition of the mycobacterium tuberculosis ENoyl-ACP reductase InhA. / Li, Huei Jiun; Lai, Cheng Tsung; Pan, Pan; Yu, Weixuan; Liu, Nina; Bommineni, Gopal R.; Garcia-Diaz, Miguel; Simmerling, Carlos; Tonge, Peter J.

In: ACS Chemical Biology, Vol. 9, No. 4, 18.04.2014, p. 986-993.

Research output: Contribution to journalArticle

Li, HJ, Lai, CT, Pan, P, Yu, W, Liu, N, Bommineni, GR, Garcia-Diaz, M, Simmerling, C & Tonge, PJ 2014, 'A structural and energetic model for the slow-onset inhibition of the mycobacterium tuberculosis ENoyl-ACP reductase InhA', ACS Chemical Biology, vol. 9, no. 4, pp. 986-993. https://doi.org/10.1021/cb400896g
Li, Huei Jiun ; Lai, Cheng Tsung ; Pan, Pan ; Yu, Weixuan ; Liu, Nina ; Bommineni, Gopal R. ; Garcia-Diaz, Miguel ; Simmerling, Carlos ; Tonge, Peter J. / A structural and energetic model for the slow-onset inhibition of the mycobacterium tuberculosis ENoyl-ACP reductase InhA. In: ACS Chemical Biology. 2014 ; Vol. 9, No. 4. pp. 986-993.
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