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J Med Chem 1994 Oct 28;37(22):3684-92

Design, synthesis, and conformational analysis of a novel macrocyclic HIV-protease inhibitor.

Podlogar BL, Farr RA, Friedrich D, Tarnus C, Huber EW, Cregge RJ, Schirlin D

Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215-6300.

Design modifications to the lead HIV-PR inhibitor 1 (MDL 73,669, Ki = 5 nM) have been postulated based on a computational model of the 1/HIV-PR complex. A novel macrocyclic inhibitor 8 (MDL 104,168) wherein the P1 and P3 side chains of the original acyclic inhibitor have been joined retains good biological activity (Ki = 20 nM). NMR analysis of the precursor alcohol (S)-7 shows the conformation of the cyclic region to be very similar to that observed in the enzyme-bound 8 as determined by the computational model. Consistency of the computational model with NMR data and in vacuo molecular dynamics simulations provide the basis for postulating further modifications of the cyclic inhibitor expected to optimize its interactions with HIV-PR.

MeSH Terms:

• Amino Acid Sequence
• Dipeptides/pharmacology
• Dipeptides/chemistry*
• Drug Design
• HIV Protease Inhibitors/pharmacology
• HIV Protease Inhibitors/chemistry*
• Models, Molecular
• Molecular Sequence Data
• Nuclear Magnetic Resonance
• Peptides, Cyclic/pharmacology
• Peptides, Cyclic/chemistry*

Substances:

• MDL 104168
• MDL 73669
• Peptides, Cyclic
• HIV Protease Inhibitors
• Dipeptides

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