Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere.
Linah N RusereGordon J LockbaumMina HenesSook-Kyung LeeEan SpielvogelDesaboini Nageswara RaoKlajdi KosovrastiEllen A NalivaikaRonald SwanstromNese Kurt YilmazCelia A SchifferAkbar AliPublished in: Journal of medicinal chemistry (2020)
The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C2-symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2' position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2' position without significantly affecting potency. However, the group on the opposite P2/P2' position had a dramatic effect on potency depending on the size and shape of the side chain. Cocrystal structures of inhibitors with wild-type HIV-1 protease revealed that the bis-THF moiety retained similar interactions as observed in the darunavir-protease complex regardless of the position on the Phe-Phe isostere. Analyses of cocrystal structures and molecular dynamics simulations provide insights into optimizing HIV-1 PIs containing bis-THF in non-sulfonamide dipeptide isosteres.
Keyphrases
- ionic liquid
- antiretroviral therapy
- hiv positive
- hiv infected
- hiv testing
- human immunodeficiency virus
- molecular dynamics simulations
- hepatitis c virus
- hiv infected patients
- hiv aids
- men who have sex with men
- high resolution
- amino acid
- south africa
- magnetic resonance imaging
- structure activity relationship
- single cell
- molecular docking
- mass spectrometry
- contrast enhanced