Development and testing of protocols for computer-aided design of peptide drugs, using oxytocin

Conformations of a model cyclic hexapeptide, CYIQNC:1H-NMR and molecular dynamics studies

“…It has been shown that the residues 4, 5 in CYIQNC sequence play important roles as the central residues in the formation of β-turns in IQNC segment, as has been shown in our studies on the cyclic hexapeptide . Such a view is consistent with the comparative studies on the conformational characterization of a cyclic ring of OT (Lippens et al, 1993;Liwo et al, 1989;Lubecka et al, 2014;Nikiforovich et al, 1979;Ward et al, 1991). The possibility of existence of type-III β-turn at the residue 4, 5 in IQNC segment in the micelle-environment has also been reported (Rodziewicz-Motowidlo et al, 2008).…”

“…Though the past NMR data on the cyclic part of the OT and its analogs revealed a β-turn at residues 3, 4, the possibilities of the occurrence of other types of conformations in different environmental conditions have also been reported, such as a turn at residues 4, 5 (Lippens et al, 1993), a γ-turn at Gln 4 (Mosberg, Hruby, & Meraldi, 1981), β-turn at 2, 3 or 4, 5 (Nikiforovich et al, 1979;Liwo et al, 1989;Ward, Chen, Platt, & Robson, 1991) with a dynamic equilibrium between β-turns at residues 2, 3; 3, 4; and 4, 5 (Liwo et al, 1996). Recently, a type-IV β-turn was also reported to be observed at residues 3, 4 (YIQN segment) in the cyclic sequence -c[CYIQNC]-PIG-NH2 -of mesotocin (a homologous cyclic sequence of OT) in water (Sikorska & Rodzeiwicz-Motowidlo, 2008) as well as in SDS micelle (Rodziewicz-Motowidlo, Sikorska, Oleszczuk, & Czaplewski, 2008), with the possibility of existence of a β-turn of type I or type III at residues 4, 5 in 3-6 segment (IQNC) in SDS micelles environment.…”

Modular Peptide Synthetases Involved in Nonribosomal Peptide Synthesis

“…The success of novel peptides depends mainly on their biological activity, and it seems unlikely that random changes would improve properties. Structural modeling tools like computer-aided drug design could be a prospect to overcome this problem and to stimulate the development of peptide-based drugs. − The emerging structural and functional capabilities of nonribosomally synthesized peptides will allow us to evaluate whether these sources can be used to create new products of biological significance.…”

“…Structural modeling tools like computer-aided drug design could be a prospect to overcome this problem and to stimulate the development of peptidebased drugs. [153][154][155] The emerging structural and functional capabilities of nonribosomally synthesized peptides will allow us to evaluate whether these sources can be used to create new products of significance. A direct approach for a targeted reprogramming of peptide synthetases could be available by defining the structural basis of substrate specificity.…”

Examination of structural characteristics of the potent oxytocin antagonists [dPen1,Pen6]-OT and [dPen1,Pen6, 5-tBuPro7]-OT by NMR, raman, CD spectroscopy and molecular modeling

“…the major (trans-) conformers of 1 and 2 suggested along with the Raman and CD data that a subset of lower-energy conformations existed with a specific disulfide geometry. Computational methods have been used extensively to search for preferred conformations for oxytocin analogs, and have resulted in the discovery of several families of stable conformations [23,[79][80][81][82][83]. In a similar fashion, a conformational search was undertaken to assess whether or not the observed data corresponded to a unique set of conformations for both analogs.…”