Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere
| Autor: | Sook-Kyung Lee, Mina Henes, Ronald Swanstrom, Celia A. Schiffer, Linah N. Rusere, Klajdi Kosovrasti, Ean Spielvogel, Akbar Ali, Gordon J. Lockbaum, Desaboini Nageswara Rao, Nese Kurt Yilmaz, Ellen A. Nalivaika |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Stereochemistry Isostere medicine.medical_treatment HIV Infections Crystallography X-Ray 01 natural sciences Cocrystal Article 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship HIV-1 protease HIV Protease Drug Discovery Side chain medicine Moiety Humans Furans Darunavir 030304 developmental biology 0303 health sciences Protease Dipeptide biology virus diseases Dipeptides HIV Protease Inhibitors 0104 chemical sciences 010404 medicinal & biomolecular chemistry HEK293 Cells chemistry Drug Design biology.protein HIV-1 Molecular Medicine medicine.drug |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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