Designing selec5ve kinase inhibitors alterna5ves

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

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...
View Full Document

{[ snackBarMessage ]}

Ask a homework question - tutors are online