Yeni aminoglikosit antibiyotiklerin NMR analizi ve amber ile tasarimi

The pH dependence on the solution structure of neamine was determined by NMRand AMBER Molecular Dynamics methods at pD=3.3, pD=6.5, and pD=7.4 at25oC in D2O. Unlike neamine structures at pD=3.3 and 6.5, which essentiallyshowed only one conformer, slowly exchaning primary, P-state, and secondary, Sstate,neamine conformers populated at ~80% and ~20%, respectively, weredetected on the NMR time scale at pD=7.4 with kinetic constants kon(P->S)=1.9771sec-1 and koff(S->P)=1.1319 sec-1. A tertiary, T state, neamine species populated at~3% was also detected by NMR at pD=~7.4. The pKa values determined arepKa1=6.44±0.13 for N3 of ring-II, pKa2=7.23±0.09 for N2? of ring-I,pKa3=7.77±0.19 for N1 of ring-II, and pKa4=8.08±0.15 for N6? of ring-I. Ring-Iand ring-II of the P-state neamine and ring-I of the S-/T-state neamine possess 4C1chair conformation between pD=3.3 and pD=7.4. In contrast, ring-II of the S-/Tstateneamine adopts 6rH1 half-chair conformation. The P- and S-states of neamineadopt a negative syn- ? glycosidic geometry. The exocyclic aminomethyl group ofring-I adopts the gt exocyclic rotamer around physiological pHs while the ggexocyclic rotamer predominates in acidic solutions (pH<4.5). The P-state neamineexist in tetra-/tri-/di-protonated states between pD=4.5 and pD=7.4 while the S-/Tstateneamine exists only in di-protonated state around physiological pDs. Theexistance of the S-/T-state neamine may facilitate binding of neamine-likeaminoglycosides by favorable entropy of binding to the A-site of 16S rRNA.Novel aminoglycoside compounds resembling the S-/T-state neamine areproposed here to evade bacterial resistance, decrease toxicity, and increasespecificity and affinity.