title: Structure-guided design of C2-symmetric HIV-1 protease inhibitors based on a pyrrolidine scaffold.
abstract: Infections with the human immunodeficiency virus, which inevitably lead to the development of AIDS, are still among the most serious global health problems causing more than 2.5 million deaths per year. In the pathophysiological processes of this pandemic, HIV protease has proven to be an invaluable drug target because of its essential role in the virus' replication process. By use of pyrrolidine as core structure, symmetric 3,4-bis-N-alkylsulfonamides were designed and synthesized enantioselectively from D-(-)-tartaric acid as a new class of HIV protease inhibitors. Structure-guided design using the cocrystal structure of an initial lead as starting point resulted in a second series of inhibitors with improved affinity. The binding modes of four representatives were determined by X-ray crystallography to elucidate the underlying factors accounting for the SAR. With this information for further rational design, the combination of suitable side chains resulted in a final inhibitor showing a significantly improved affinity of K(i) = 74 nM.
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, Marburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Blum
authors.forename: Jark
authors.initials: J
authors.lastname: Böttcher
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.forename: Wibke E
authors.initials: WE
authors.lastname: Diederich
mesh_terms: D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D015195:Drug Design; D016333:HIV Protease / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D011759:Pyrrolidines; D016333:HIV Protease; C032519:pyrrolidine