title: C2-symmetric inhibitors of Plasmodium falciparum plasmepsin II: synthesis and theoretical predictions.
abstract: A series of C(2)-symmetric compounds with a mannitol-based scaffold has been investigated, both theoretically and experimentally, as Plm II inhibitors. Four different stereoisomers with either benzyloxy or allyloxy P1/P1' side chains were studied. Computational ranking of the binding affinities of the eight compounds was carried out using the linear interaction energy (LIE) method relying on a complex previously determined by crystallography. Within both series of isomers the theoretical binding energies were in agreement with the enzymatic measurements, illustrating the power of the LIE method for the prediction of ligand affinities prior to synthesis. The structural models of the enzyme-inhibitor complexes obtained from the MD simulations provided a basis for interpretation of further structure-activity relationships. Hence, the affinity of a structurally similar ligand, but with a different P2/P2' substituent was examined using the same procedure. The predicted improvement in binding constant agreed well with experimental results.
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23, Uppsala, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Ersmark
authors.forename: Isabella
authors.initials: I
authors.lastname: Feierberg
authors.forename: Sinisa
authors.initials: S
authors.lastname: Bjelic
authors.forename: Johan
authors.initials: J
authors.lastname: Hultén
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Johan
authors.initials: J
authors.lastname: Aqvist
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D001665:Binding Sites; D007189:Indans / Q000737:chemistry / Q000494:pharmacology; D008353:Mannitol / Q000737:chemistry*; D008956:Models, Chemical; D010963:Plasmodium falciparum / Q000201:enzymology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015800:Protozoan Proteins; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D000962:Antimalarials; D007189:Indans; D011480:Protease Inhibitors; D015800:Protozoan Proteins; C116915:aminoindanol; D008353:Mannitol; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II