Kinase_Lecture_MedChem2

Designing selec5ve kinase inhibitors alterna5ves

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Unformatted text preview: s no steric effect • Methyl group is replaced by a chloro subs4tuent • Chlorine and methyl group have similar sizes and lipophilici4es • Chlorine acts as a bio- isotere for the methyl group • Chlorine is resistant to oxida4on • Compound is less ac4ve in vitro, but more ac4ve in vivo Gefi4nib (Iressa) Drug design F F Morpholine HN 4 N CH3 6 HN OMe OMe N N 7 I; IC50 5 nM OMe Cl HN Cl 4 6 N3 OMe IV: IC50 9 nM N O N Spacer 1 N O 7 OMe Gefi4nib Notes • Morpholine ring increases water solubility • Morpholine nitrogen allows genera4on of water soluble amine salts • Spacer allows morpholine to protrude out of the ac4ve site • Remains solvated when the drug is bound • Avoids a desolva4on penalty Ionisable Gefi4nib (Iressa) Binding interac4ons • Iden4fied by a molecular modelling experiment • Gefi4nib is docked with a model binding site • Binds to the ATP binding site • Aniline ring occupies the normally vacant hydrophobic pocket opposite the ribose binding pocket • Quinazoline binds to the same region as the purine ring of ATP F Thr-830 OH2 Hydrophobic pocket H HBA N N O Cl O N HBA Met-769 OMe N Cleft Kinase inhibitors: ge...
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