PMID- 9770304
OWN - NLM
STAT- MEDLINE
DCOM- 19981113
LR  - 20191102
IS  - 0095-2338 (Print)
IS  - 0095-2338 (Linking)
VI  - 38
IP  - 5
DP  - 1998 Sep-Oct
TI  - Four-dimensional quantitative structure-activity relationship analysis of a 
      series of interphenylene 7-oxabicycloheptane oxazole thromboxane A2 receptor 
      antagonists.
PG  - 925-38
AB  - A series of 39 (a training set of 29 and a test set of 10) interphenylene 
      7-oxabicyclo [2.2.1]heptane oxazole thromboxane A2 (TXA2) receptor antagonists 
      were studied using four-dimensional quantitative structure-activity relationship 
      (4D-QSAR) analysis. Two thousand conformations of each analogue were sampled to 
      generate a conformational energy profile (CEP) from a molecular dynamic 
      simulation (MDS) of 100,000 trajectory states. Each conformation was placed in a 
      grid cell lattice for each of six trial alignments. Cubic grid cell sizes of 1 
      and 2 A were considered. The frequency of occupation of each grid cell was 
      computed for each of seven types of pharmacophoric group classes of atoms of each 
      compound. These grid cell occupancy descriptors (GCODs) were then used as 
      independent variables in constructing three-dimensional (3D)-QSAR models after 
      data reduction. The types of data reduction included doing no reducing, reduction 
      based on individual GCOD correlation with activity, and reduction from minimum 
      variance constraints over the GCOD population. The 3D-QSAR models were generated 
      and evaluated by a scheme that combines a genetic algorithm (GA) optimization 
      with partial least squares (PLS) regression. The 3D-QSAR models were evaluated by 
      cross-validation using the leave-one-out technique. The cross-validated 
      correlation coefficient, Q2, ranged from 0.27 to 0.86. The models are not from 
      chance correlation because a scrambled data set was generated and evaluated (Q2 = 
      0.25-0.37). A composite 3D-QSAR model was constructed using the best models 
      derived from GCODs of both 1 and 2 A grid cell size lattices. The 3D-QSAR models 
      provide detailed 3D pharmacophore requirements in terms of atom types and 
      corresponding locations needed for high TXA2 inhibition activity. Specific sites 
      in space that should not be occupied by an active inhibitor are also specified. 
      The GCOD measures for the compounds in the training set permit reference points 
      regarding which pharmacophore sites can provide the largest boosts in inhibition 
      activity relative to the existing analogues.
FAU - Albuquerque, M G
AU  - Albuquerque MG
AD  - Laboratory of Molecular Modeling and Design, College of Pharmacy, University of 
      Illinois at Chicago 60612-7231, USA.
FAU - Hopfinger, A J
AU  - Hopfinger AJ
FAU - Barreiro, E J
AU  - Barreiro EJ
FAU - de Alencastro, R B
AU  - de Alencastro RB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - J Chem Inf Comput Sci
JT  - Journal of chemical information and computer sciences
JID - 7505012
RN  - 0 (Oxazoles)
RN  - 0 (Receptors, Thromboxane)
SB  - IM
MH  - *Drug Design
MH  - Models, Chemical
MH  - Oxazoles/*chemical synthesis/pharmacology
MH  - Protein Conformation
MH  - Receptors, Thromboxane/*antagonists & inhibitors
MH  - Structure-Activity Relationship
EDAT- 1998/10/14 00:00
MHDA- 1998/10/14 00:01
CRDT- 1998/10/14 00:00
PHST- 1998/10/14 00:00 [pubmed]
PHST- 1998/10/14 00:01 [medline]
PHST- 1998/10/14 00:00 [entrez]
AID - 10.1021/ci980093s [doi]
PST - ppublish
SO  - J Chem Inf Comput Sci. 1998 Sep-Oct;38(5):925-38. doi: 10.1021/ci980093s.