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.