QSAR in Development of Antidepressants
QSAR in Development of Antidepressants QSAR in Development of Antidepressants
Leads and biological activity IC 50 (nM) Drug TCAs imipramine nortriptyline protriptyline trimipramine Second generation Amoxapine mirtazapine venlafazine fluoxetine fluvoxamine paroxetine sertaline Norepinephrine 25 6 10 5000 25 40 300 200 500 70 300 5-HT 50 200 250 10000 600 20000 50 15 5 1 4
QSAR Design • Create training set – consisting of known antidepressant and biological activity • activity –log IC 50 – structures built in MOE – 20 current antidepressant • all descriptors for Cerius2 used – except alignment family • Generate QSAR equation – Genetic Function Approximation(GFA) • Activity independent variable • Descriptors dependent variable • Validate the equation – Test set • 5 other antidepressant with known biological activity • Predict activity – New leads
- Page 1 and 2: The Next Generation of Antidepressa
- Page 3 and 4: Depression as a Disease • 1 out 5
- Page 5 and 6: Serotonin Hypothesis • serotonerg
- Page 7 and 8: Serotonin effect Phil Skolnick, P.
- Page 9: Project Aim • explore a faster ac
- Page 13 and 14: Why use GFA • builds multiple mod
- Page 15 and 16: • r 2 =.87 QSAR results • valid
- Page 17 and 18: Strategy Nh 2 fluoxetine F Cl O H N
- Page 19 and 20: Synthetic scheme S antidepressants
- Page 21 and 22: Synthetic scheme
- Page 23: References • Phil Skolnick, P. P.
<strong>QSAR</strong> Design<br />
• Create tra<strong>in</strong><strong>in</strong>g set<br />
– consist<strong>in</strong>g <strong>of</strong> known antidepressant and biological activity<br />
• activity –log IC 50<br />
– structures built <strong>in</strong> MOE<br />
– 20 current antidepressant<br />
• all descriptors for Cerius2 used<br />
– except alignment family<br />
• Generate <strong>QSAR</strong> equation<br />
– Genetic Function Approximation(GFA)<br />
• Activity <strong>in</strong>dependent variable<br />
• Descriptors dependent variable<br />
• Validate the equation<br />
– Test set<br />
• 5 other antidepressant with known biological activity<br />
• Predict activity<br />
– New leads
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