Toward engineering efficient peptidomimetics. Screening conformational landscape of two modified dehydroaminoacids

Abstract

Effective peptidomimetics should posses structural rigidity and appropriate interaction pattern leading to potential spatial and electronic matching to the target receptor site. Rational design of such small bioactive molecules could push chemical synthesis and molecular modeling toward faster progress in medicinal chemistry. Conformational properties of N-t-butoxycarbonyl-glycine-(E/Z)-dehydrophenylalanine N',N'-dimethylamides (Boc-Gly-(E/Z)-ΔPhe-NMe2 ) in chloroform were studied by NMR and IR spectroscopy. The experimental findings were supported by extensive calculations at DFT(B3LYP, M06-2X) and MP2 levels of theory and the β-turn tendency for both isomers of the studied dipeptide were determined in vacuum and in solution. The theoretical data and experimental IR results were used as an additional information for the NMR-based determination of the detailed solution conformations of the peptides. The obtained results reveal that N-methylation of C-terminal amide group changes dramatically the conformational properties of studied dehydropeptides. Theoretical conformational analysis reveals that the tendency to adopt β-turn conformations is much weaker for the N-methylated Z isomer (Boc-Gly-(Z)-ΔPhe-NMe2 ), both in vacuum and in polar environment. On the contrary, N-methylated E isomer (Boc-Gly-(E)-ΔPhe-NMe2 ) can easily adopt β-turn conformation, but the backbone torsion angles (φ1, ψ1, φ2, ψ2) are off the limits for common β-turn types.

Halogen effect on structure and 13C NMR chemical shift of 3,6‐disubstituted‐N‐alkyl carbazoles

“…Single‐point nonrelativistic shielding calculations were performed with VSXC density functional and with modified STO‐3G mag basis set . Both the selected VSXC density functional and Leszczynki's basis set were recently showed advantageous in predicting carbon chemical shifts . Theoretical chemical shifts (in ppm) were referenced to benzene (as secondary reference) and to tetramethylosilane calculated at the same level of theory: …”

Bulky α,β-dehydroamino acids: their occurrence in nature, synthesis, and applications

“…The results indicated that N-methylation of the C-terminal amide has a pronounced effect on the conformations of these dipeptides, and that E isomer 164 can more readily adopt a conformation resembling a b-turn. 143 Malek and Gackowski used surface-enhanced Raman spectroscopy to study the interactions of Z-DPhe tripeptides 166 and EDPhe tripeptides 167 (Fig. 46) with a silver electrode.…”

DFT studies on armchair (5, 5) SWCNT functionalization. Modification of selected structural and spectroscopic parameters upon two-atom molecule attachment

“…Its excellent performance was recently confirmed. [47][48][49] The nuclear magnetic shielding tensor ij  (in ppm) of i-th nucleus [29,50,51] was calculated as a second derivative of the total energy (E) with respect to nuclear moment ( i  ) and magnetic field (B j ):…”