Fragment-based drug discovery using a multidomain, parallel MD-MM/PBSA screening protocol

Tian Zhu, Hyun Lee, Hao Lei, Christopher Jones, Kavankumar Patel, Michael E. Johnson, Kirk Hevener

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

We have developed a rigorous computational screening protocol to identify novel fragment-like inhibitors of N5-CAIR mutase (PurE), a key enzyme involved in de novo purine synthesis that represents a novel target for the design of antibacterial agents. This computational screening protocol utilizes molecular docking, graphics processing unit (GPU)-accelerated molecular dynamics, and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) free energy estimations to investigate the binding modes and energies of fragments in the active sites of PurE. PurE is a functional octamer comprised of identical subunits. The octameric structure, with its eight active sites, provided a distinct advantage in these studies because, for a given simulation length, we were able to place eight separate fragment compounds in the active sites to increase the throughput of the MM/PBSA analysis. To validate this protocol, we have screened an in-house fragment library consisting of 352 compounds. The theoretical results were then compared with the results of two experimental fragment screens, Nuclear Magnetic Resonance (NMR) and Surface Plasmon Resonance (SPR) binding analyses. In these validation studies, the protocol was able to effectively identify the competitive binders that had been independently identified by experimental testing, suggesting the potential utility of this method for the identification of novel fragments for future development as PurE inhibitors.

Original languageEnglish (US)
Pages (from-to)560-572
Number of pages13
JournalJournal of Chemical Information and Modeling
Volume53
Issue number3
DOIs
StatePublished - Mar 25 2013
Externally publishedYes

Fingerprint

Molecular mechanics
mechanic
Screening
Intramolecular Transferases
drug
Bactericides
energy
Surface plasmon resonance
Free energy
Binders
Molecular dynamics
Enzymes
Throughput
Nuclear magnetic resonance
Anti-Bacterial Agents
simulation
Testing
Drug Discovery
AICA ribonucleotide
purine

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

Fragment-based drug discovery using a multidomain, parallel MD-MM/PBSA screening protocol. / Zhu, Tian; Lee, Hyun; Lei, Hao; Jones, Christopher; Patel, Kavankumar; Johnson, Michael E.; Hevener, Kirk.

In: Journal of Chemical Information and Modeling, Vol. 53, No. 3, 25.03.2013, p. 560-572.

Research output: Contribution to journalArticle

Zhu, Tian ; Lee, Hyun ; Lei, Hao ; Jones, Christopher ; Patel, Kavankumar ; Johnson, Michael E. ; Hevener, Kirk. / Fragment-based drug discovery using a multidomain, parallel MD-MM/PBSA screening protocol. In: Journal of Chemical Information and Modeling. 2013 ; Vol. 53, No. 3. pp. 560-572.
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