Using theory to reconcile experiment : The structural and thermodynamic basis of ligand recognition by phenylethanolamine N -methyltransferase (PNMT)

Nair, Pramod C., Malde, Alpeshkumar K. and Mark, Alan E. (2011) Using theory to reconcile experiment : The structural and thermodynamic basis of ligand recognition by phenylethanolamine N -methyltransferase (PNMT). Journal of Chemical Theory and Computation, 7 5: 1458-1468. doi:10.1021/ct1007229


Author Nair, Pramod C.
Malde, Alpeshkumar K.
Mark, Alan E.
Title Using theory to reconcile experiment : The structural and thermodynamic basis of ligand recognition by phenylethanolamine N -methyltransferase (PNMT)
Journal name Journal of Chemical Theory and Computation   Check publisher's open access policy
ISSN 1549-9618
1549-9626
Publication date 2011-05-01
Sub-type Article (original research)
DOI 10.1021/ct1007229
Volume 7
Issue 5
Start page 1458
End page 1468
Total pages 11
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2012
Language eng
Formatted abstract
A fundamental challenge in computational drug design is the availability of reliable and validated experimental binding and structural data against which theoretical calculations can be compared. In this work a combination of molecular dynamics (MD) simulations and free energy calculations has been used to analyze the structural and thermodynamic basis of ligand recognition by phenylethanolamine N-methyltransferase (PNMT) in an attempt to resolve uncertainties in the available binding and structural data. PNMT catalyzes the conversion of norepinephrine into epinephrine (adrenaline), and inhibitors of PNMT are of potential therapeutic importance in Alzheimer's and Parkinson's disease. Excellent agreement between the calculated and recently revised relative binding free energies to human PNMT was obtained with the average deviation between the calculated and the experimentally determined values being only 0.8 kJ/mol. In this case, the variation in the experimental data over time is much greater than the uncertainties in the theoretical estimates. The calculations have also enabled the refinement of structure-activity relationships in this system, to understand the basis of enantiomeric selectivity of substitution at position three of tetrahydroisoquinoline and to identify the role of specific structural waters. Finally, the calculations suggest that the preferred binding mode of trans-(1S,2S)-2-amino-1-tetralol is similar to that of its epimer cis-(1R,2S)-2-amino-1-tetralol and that the ligand does not adopt the novel binding mode proposed in the pdb entry 2AN5. The work demonstrates how MD simulations and free energy calculations can be used to resolve uncertainties in experimental binding affinities, binding modes, and other aspects related to X-ray refinement and computational drug design.
Keyword Display Remarkable Potency
Free-energy Calculations
Selective Inhibitors
Molecular-dynamics
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Wed, 28 Sep 2011, 21:42:53 EST by Dr Alpeshkumar Malde on behalf of School of Chemistry & Molecular Biosciences