Use of substituted oxamide structure in designing pseudo-symmetric HIV protease inhibitors to employ multiple bridging water molecules

Hidaka, Koshi*; Toda, Yuki*; Adachi, Motoyasu; Kuroki, Ryota; Kiso, Yoshiaki*

Molecular dynamic simulations of the inhibitor suggested existence of additional stable bridging water molecules to support the binding with mutated proteases. To increase the numbers of bridging water molecules, we replaced amide with sulfonyl and oxamide structures at both terminals of pseudo-symmetric peptides based on HMC. In summary, oxamide modifications resulted in a moderate activity loss against lopinavir-resistant mutations compared to inhibitors without oxamide. This method to accompany multiple bridging water molecules could be applicable to design protease inhibitors to defeat the drug resistance from amino acid mutations.