Hiv-1 Protease And Its Inhibitors

HIV-1 protease (HIV-1 PR), one of the three enzymes encoded by the viral genome and vital for its replication, is natural target for chemotherapy. The three-dimensional Xray structure of the native form, and of its complexes with various inhibitors, provide a basis for understanding the physicochemical properties of the protease. Formation of the catalytically active homodimeric form of the protease, and of its complexes with inhibitors, may be determined by two physically different types of interactions: electrostatic and hydrophobic. Selected problems related to rational drug design will be discussed; rigidity and flexibility of the enzyme; analysis of electrostatic and hydrophobic interactions in the interface region; dissociative inhibition in the intertwining region; electrostatic field of the binding site; protonation state of the catalytic aspartates; location of internal water molecules; presentation of selected inhibitors. From a methodological point of view, HIV-1 PR is an excellent object for testing different theoretical methods applied to computer-aided drug design.