Abstract
Selective S1P1 receptor agonists have therapeutic potential to treat a variety of immune-mediated diseases. A series of 2-imino-thiazolidin-4-one derivatives displaying potent S1P1 receptor agonistic activity were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated as well as some measures including region focusing, progressive scrambling, bootstraping and leave-group-out. The satisfactory CoMFA model predicted a q2 value of 0.751 and an r2 value of 0.973, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic, hydrophobic and H-bond donor descriptors, predicted a q2 value of 0.739 and an r2 value of 0.923. The models were graphically interpreted using contour plots which gave more insight into the structural requirements for increasing the activity of a compound, providing a solid basis for future rational design of more active S1P1 receptor agonists.
Highlights
Sphingosine-1-phosphate (S1P), a widespread lysophospholipid, binds five specific G-protein coupled receptors (S1P1-S1P5) [1,2,3,4] and exerts a variety of biological activities such as vascular maturation, cell survival, proliferation, differentitation, migration and chemotaxis [5,6,7]
Many researchers [18,19] have carried out quantitative structure activity relationship (QSAR) studies on thiazolidin-4-ones as anti-HIV agents, but the present work reports the first application of QSAR to study thiazolidin-4-ones as potent S1P1 receptor agonists [8]
We studied 61 2-imino-thiazolidin-4-one derivatives using comparative molecular field analysis (CoMFA) [20] and comparative molecular similarity indices analysis (CoMSIA) [21]
Summary
Sphingosine-1-phosphate (S1P), a widespread lysophospholipid, binds five specific G-protein coupled receptors (S1P1-S1P5) [1,2,3,4] and exerts a variety of biological activities such as vascular maturation, cell survival, proliferation, differentitation, migration and chemotaxis [5,6,7]. The S1P1 receptor only couples to Gαi/o while the other S1P receptors are promiscuous with respect to G-protein coupling, activating G12/13 in addition to Gαi/o and Gαq in the case of S1P2 and S1P3 [8]. Selective S1P1 receptor agonists are promisingly developed as a novel immunomodulator. S1P1 receptor has been considered a potential target for a variety of immune-mediated diseases, including rheumatoid arthritis, psoriasis and multiple sclerosis disease. A novel class of S1P1 receptor agonists based on the
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