PMID- 16988958
OWN - NLM
STAT- MEDLINE
DCOM- 20070411
LR  - 20151119
IS  - 0192-8651 (Print)
IS  - 0192-8651 (Linking)
VI  - 27
IP  - 16
DP  - 2006 Dec
TI  - Coupled atomic charge selectivity for optimal ligand-charge distributions at 
      protein binding sites.
PG  - 1899-907
AB  - Charge optimization as a tool for both analyzing and enhancing binding 
      electrostatics has become an attractive approach over the past few years. An 
      interesting feature of this method for molecular design is that it provides not 
      only the optimal charge magnitudes, but also the selectivity of a particular 
      atomic center for its optimal charge. The current approach to compute the charge 
      selectivity at a given atomic center of a ligand in a particular binding process 
      is based on the binding-energy cost incurred upon the perturbation of the optimal 
      charge distribution by a unit charge at the given atomic center, while keeping 
      the other atomic partial charges at their optimal values. A limitation of this 
      method is that it does not take into account the possible concerted changes in 
      the other atomic charges that may incur a lower energetic cost than perturbing a 
      single charge. Here, we describe a novel approach for characterizing charge 
      selectivity in a concerted manner, taking into account the coupling between the 
      ligand charge centers in the binding process. We apply this novel charge 
      selectivity measure to the celecoxib molecule, a nonsteroidal anti-inflammatory 
      agent binding to cyclooxygenase 2 (COX2), which has been recently shown to also 
      exhibit cross-reactivity toward carbonic anhydrase II (CAII), to which it binds 
      with nanomolar affinity. The uncoupled and coupled charge selectivity profiles 
      over the atomic centers of the celecoxib ligand, binding independently to COX2 
      and CAII, are analyzed comparatively and rationalized with respect to available 
      experimental data. Very different charge selectivity profiles are obtained for 
      the uncoupled versus coupled selectivity calculations.
FAU - Bhat, Sathesh
AU  - Bhat S
AD  - Department of Biochemistry, McGill University, 3655 Sir William Osler, Montreal, 
      Quebec H3G 1Y6, Canada.
FAU - Sulea, Traian
AU  - Sulea T
FAU - Purisima, Enrico O
AU  - Purisima EO
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Comput Chem
JT  - Journal of computational chemistry
JID - 9878362
RN  - 0 (Cyclooxygenase 2 Inhibitors)
RN  - 0 (Ligands)
RN  - 0 (Pyrazoles)
RN  - 0 (Sulfonamides)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 4.2.1.- (Carbonic Anhydrase II)
RN  - JCX84Q7J1L (Celecoxib)
SB  - IM
MH  - Binding Sites
MH  - Carbonic Anhydrase II/*chemistry
MH  - Celecoxib
MH  - Computer Simulation
MH  - Cyclooxygenase 2/*chemistry
MH  - Cyclooxygenase 2 Inhibitors/*chemistry
MH  - Ligands
MH  - *Models, Chemical
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Protein Binding
MH  - Pyrazoles/*chemistry
MH  - Structure-Activity Relationship
MH  - Sulfonamides/*chemistry
EDAT- 2006/09/22 09:00
MHDA- 2007/04/12 09:00
CRDT- 2006/09/22 09:00
PHST- 2006/09/22 09:00 [pubmed]
PHST- 2007/04/12 09:00 [medline]
PHST- 2006/09/22 09:00 [entrez]
AID - 10.1002/jcc.20481 [doi]
PST - ppublish
SO  - J Comput Chem. 2006 Dec;27(16):1899-907. doi: 10.1002/jcc.20481.