PHAR 505 Lecture Notes - Lecture 11: Hiv-1 Protease, Reaction Intermediate, Chemical Stability
13 Nov 2017
School
Department
Course
Professor
Document Summary
Ts analogues which mimic the tight binding of ts to enzyme catalysts, have been designed in combined experimental/computational studies. Free energy profile (right) that shows how enzymatic catalysis of the formulation of an unstable reaction intermediate, such as carbanion or carbocation, can result from strong specific molecular recognition of the. A significant fraction of this ts binding energy can be recovered in the binding of ts analogues. Analogues of the ts can bind more tightly than substrates for many reasons: chemical stability, not a substrate of the enzyme, thus not degraded, more drug-like properties. They show promise for drug development for several targets. Protease, such as hiv-1 protease are good examples of that. Proposed mechanism for hiv pr catalysis based on kinetic and structural data. Non-cleavable intermediate isostere developed for the synthesis of hiv pr inhibitors. Using a combination of experimentally measured kies and theoretical calculations, the structure of the rate- limiting ts in the hiv-1 protease reaction was resolved.
