Structure-based drug design identifies novel LPA3 antagonists.
Compound 5 ([5-(3-nitrophenoxy)-1,3-dioxo-1,3-dihydro-2-isoindol-2-yl]acetic acid) was identified as a weak selective LPA(3) antagonist (IC(50)=4504 nM) in a virtual screening effort to optimize a dual LPA(2 and 3) antagonist. Structure-based drug design techniques were used to prioritize similarity search matches of compound 5. This strategy rapidly identified 10 novel antagonists. The two most efficacious compounds identified inhibit activation of the LPA(3) receptor by 200 nM LPA with IC(50) values of 752 nM and 2992 nM. These compounds additionally define changes to our previously reported pharmacophore that will improve its ability to identify more potent and selective LPA(3) receptor antagonists. The results of the combined computational and experimental screening are reported.
Department of Chemistry and Computational Research on Materials Institute, The University of Memphis, Memphis, TN 38152, United States.
James I
JI
Fells
Ryoko
R
Tsukahara
Jianxiong
J
Liu
Gabor
G
Tigyi
Abby L
AL
Parrill
D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D054833:Isoindoles; D049368:Receptors, Lysophosphatidic Acid