De Novo Design And Synthesis Of Nonpeptidic Inhibitors Based On The Structure Of HIV-1 Protease

Lead discovery is an important aspect of drug research and development. Leads derive from active substances, natural ligands or some known substrates usually. Random screen has been the traditional method to find leads for long time. Rational method compared to random screen is yet being developed. In last decade, some new compounds as medicine were designed based on the template of receptor structure or pharmacophore, thereby the method so-called structure-based molecular design was established. Two approaches in structure-based lead design can be distinguished: de novo design and searching three dimensional structures. 3D searching, compared to de novo design, can hardly find new structures according to pharmacophore and limited database though it can retrieve similar structures to known active compounds. A lot of programs of de novo design in high automatic degree can create diverse structures, but few of them as effective compounds can be found in literature. FKBP-12 (FK-506 binding protein) ligands were designed by LUDI program successfully, but artificial selection of frame and substitutes was carried out necessarily. Artificial interference can not be evaded in molecular design at present. In addition, designer can only see the evaluated result when design leads by whatever de novo design program, not being able to know the details of evaluation which is run in background by computer.I have explored and established originally a tactic named interactive visual docking-growing method which combines visual molecular docking and artificial de novo design, and I have designed leads based on HIV-1 protease by this method. After design, I synthesized the potential designed molecules according to the principle "from design to synthesis". The process of design is computer-aided, but not computer-controlled. It is controlled by designer in front of the screen. One can get optical feedback real time in each step of molecular design by visual docking manoeuver. Rational interference from designer makes designed molecules more reasonable and novel. Using docking-growing method proposed in this paper, one can design leads with...