1W5W

HIV-1 protease in complex with fluoro substituted diol-based C2- symmetric inhibitor

Summary for 1W5W

• Entry DOI: 10.2210/pdb1w5w/pdb
• Related: 1AJV 1AJX 1AXA 1BQM 1BQN 1D4H 1D4I 1D4J 1DLO 1DW6 1EBK 1EBW 1EBY 1EBZ 1EC0 1EC1 1EC2 1EC3 1EET 1HBV 1HEF 1HEG 1HIH 1HMV 1HNI 1HNV 1HOS 1HPS 1HPZ 1HQE 1HQU 1HRH 1HTE 1HTF 1HTG 1HVK 1HVP 1HVU 1HYS 1IKV 1IKW 1IKX 1IKY 1J5O 1MER 1MES 1MET 1MEU 1N5Y 1N6Q 1QE1 1QMC 1R0A 1RDH 1RTD 1RVL 1RVM 1RVN 1RVO 1RVP 1RVQ 1RVR 1S6P 1S6Q 1S9E 1S9G 1SBG 1SUQ 1SV5 1T03 1T05 1TV6 1TVR 1UWB 1W5V 2HMI 3HVT 3TLH
• Descriptor: POL POLYPROTEIN, (2R,3R,4R,5R)-2,5-BIS[(2,4-DIFLUOROBENZYL)OXY]-3,4-DIHYDROXY-N,N'-BIS[(1R,2S)-2-HYDROXY-2,3-DIHYDRO-1H-INDEN-1-YL]HEXAN EDIAMIDE (3 entities in total)
• Functional Keywords: hydrolase/hydrolase inhibitor, hydrolase, dimer, protein-inhibitor complex, hydrolase-hydrolase inhibitor complex
• Biological source: HUMAN IMMUNODEFICIENCY VIRUS (HIV-1)
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366
• Total number of polymer chains: 2
• Total formula weight: 24780.81

Authors

Lindberg, J.,Pyring, D.,Loewgren, S.,Rosenquist, A.,Zuccarello, G.,Kvarnstroem, I.,Zhang, H.,Vrang, L.,Claesson, B.,Hallberg, A.,Samuelsson, B.,Unge, T. (deposition date: 2004-08-10, release date: 2004-12-22, Last modification date: 2024-05-08)

Primary citation

Lindberg, J.,Pyring, D.,Loewgren, S.,Rosenquist, A.,Zuccarello, G.,Kvarnstroem, I.,Zhang, H.,Vrang, L.,Claesson, B.,Hallberg, A.,Samuelsson, B.,Unge, T.
Symmetric Fluoro-Substituted Diol-Based HIV Protease Inhibitors. Ortho-Fluorinated and Meta-Fluorinated P1/P1'-Benzyloxy Side Groups Significantly Improve the Antiviral Activity and Preserve Binding Efficacy
Eur.J.Biochem., 271:4594-, 2004

PubMed Abstract: HIV-1 protease is a pivotal enzyme in the later stages of the viral life cycle which is responsible for the processing and maturation of the virus particle into an infectious virion. As such, HIV-1 protease has become an important target for the treatment of AIDS, and efficient drugs have been developed. However, negative side effects and fast emerging resistance to the current drugs have necessitated the development of novel chemical entities in order to exploit different pharmacokinetic properties as well as new interaction patterns. We have used X-ray crystallography to decipher the structure-activity relationship of fluoro-substitution as a strategy to improve the antiviral activity and the protease inhibition of C2-symmetric diol-based inhibitors. In total we present six protease-inhibitor complexes at 1.8-2.3 A resolution, which have been structurally characterized with respect to their antiviral and inhibitory activities, in order to evaluate the effects of different fluoro-substitutions. These C2-symmetric inhibitors comprise mono- and difluoro-substituted benzyloxy side groups in P1/P1' and indanoleamine side groups in P2/P2'. The ortho- and meta-fluorinated P1/P1'-benzyloxy side groups proved to have the most cytopathogenic effects compared with the nonsubstituted analog and related C2-symmetric diol-based inhibitors. The different fluoro-substitutions are well accommodated in the protease S1/S1' subsites, as observed by an increase in favorable Van der Waals contacts and surface area buried by the inhibitors. These data will be used in the development of potent inhibitors with different pharmacokinetic profiles towards resistant protease mutants.

PubMed: 15560801
DOI: 10.1111/J.1432-1033.2004.04431.X

Experimental method

X-RAY DIFFRACTION (1.8 Å)