C2bip#080053 643..652

C ombination therapy that includes inhibitors of HIV-1 protease (HIVp) are necessary to treat HIV-infected patients. Currently, there are eight peptidic and two nonpeptidic drugs on the market that competitively bind in the active site and inhibit HIVp by mimicking substrates and the transition state of peptide cleavage. The discovery of novel inhibitors is still a very active area of research due to the associated toxicity, poor pharmacokinetic properties, and resistance that has developed to the existing drugs. HIVp is a C2-symmetric dimer with its active site located at the dimer interface. The central active site is covered by two glycine-rich, antiparallel b-hairpins, referred to as the ‘‘flaps’’ (residues 43–58). The conformational behavior of the flap region has been extensively studied. The largest populated states are thought to be closed, semiopen, and open. The semiopen conformation is the most prevalent in the apo state, and the closed state is seen when competitive inhibitors are bound in the active site. Two groups have used Langevin Dynamics (LD) simulations to demonstrate the extensive conformational sampling available to the flaps in the apo state. Upon introduction of a ligand into the active site of a semiopen conformation, LD simulations have shown that the ligand will induce the flaps to close and replicate key hydrogen bonds seen in bound crystal structures. Here, we present a novel mode of action for HIVp inhibitors: modulating the conformation behavior of HIVp by targeting the flap-recognition site. Upon substrate binding, each flap closes down and positions its flap tip (residues 49–52) in a highly conserved region on the opposite-side monomer, see Figure 1a. This region can also be called the ‘‘eye’’ from recent HIVp naming convention (based on the backbone of the ABSTRACT: