Design and synthesis of sulfoximine based inhibitors for HIV-1 protease.
A new class of potent sulfoximine inhibitors for HIV-1 protease has been designed and synthesized. Substitution of the sulfoximine moiety into different parent compounds yields different inhibition effects. While our previously studied sulfoximine-based inhibitors display potency of 2.5 nM (IC(50)) against HIV-1 protease, introduction of the sulfoximine moiety into the asymmetric Indinavir yielded only micromolar inhibition. Docking studies showed structural variations in their modes of binding which explains this unexpected observation. The implication of these observations in the development of other sulfoximine inhibitors is discussed.
Raza
Abbas
A
Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, USA.
Sham
Yuk Yin
YY
Vince
Robert
R
D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D007097:Imines / Q000737:chemistry*; D019469:Indinavir / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D015394:Molecular Structure; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000737:chemistry*
D017320:HIV Protease Inhibitors; D007097:Imines; D013454:Sulfoxides; D019469:Indinavir; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1