6PJB
HIV-1 Protease NL4-3 WT in Complex with Lopinavir
Summary for 6PJB
| Entry DOI | 10.2210/pdb6pjb/pdb |
| Descriptor | Protease NL4-3, SULFATE ION, N-{1-BENZYL-4-[2-(2,6-DIMETHYL-PHENOXY)-ACETYLAMINO]-3-HYDROXY-5-PHENYL-PENTYL}-3-METHYL-2-(2-OXO-TETRAHYDRO-PYRIMIDIN-1-YL)-BUTYRAMIDE, ... (4 entities in total) |
| Functional Keywords | hiv, nl4-3 protease, drug resistance, protease inhibitor, hydrolase inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Human immunodeficiency virus 1 |
| Total number of polymer chains | 2 |
| Total formula weight | 23060.97 |
| Authors | Lockbaum, G.J.,Rusere, L.N.,Henes, M.,Kosovrasti, K.,Lee, S.K.,Spielvogel, E.,Nalivaika, E.A.,Swanstrom, R.,KurtYilmaz, N.,Schiffer, C.A.,Ali, A. (deposition date: 2019-06-28, release date: 2020-07-01, Last modification date: 2023-10-11) |
| Primary citation | Rusere, L.N.,Lockbaum, G.J.,Henes, M.,Lee, S.K.,Spielvogel, E.,Rao, D.N.,Kosovrasti, K.,Nalivaika, E.A.,Swanstrom, R.,Kurt Yilmaz, N.,Schiffer, C.A.,Ali, A. Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere. J.Med.Chem., 63:8296-8313, 2020 Cited by PubMed Abstract: The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C-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. PubMed: 32672965DOI: 10.1021/acs.jmedchem.0c00529 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.984 Å) |
Structure validation
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