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Improved Cyclodextrin‐Based Receptors for Camptothecin by Inverse Virtual Screening
Author(s) -
Steffen Andreas,
Thiele Carolin,
Tietze Simon,
Strassnig Christian,
Kämper Andreas,
Lengauer Thomas,
Wenz Gerhard,
Apostolakis Joannis
Publication year - 2007
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200700661
Subject(s) - camptothecin , virtual screening , chemistry , docking (animal) , combinatorial chemistry , autodock , receptor , cyclodextrin , stereochemistry , computational chemistry , molecular dynamics , organic chemistry , biochemistry , medicine , nursing , in silico , gene
We report the computer‐aided optimization of a synthetic receptor for a given guest molecule, based on inverse virtual screening of receptor libraries. As an example, a virtual set of β‐cyclodextrin (β‐CD) derivatives was generated as receptor candidates for the anticancer drug camptothecin. We applied the two docking tools AutoDock and GlamDock to generate camptothecin complexes of every candidate receptor. Scoring functions were used to rank all generated complexes. From the 10 % top‐ranking candidates nine were selected for experimental validation. They were synthesized by reaction of heptakis‐[6‐deoxy‐6‐iodo]‐β‐CD with a thiol compound to form the hepta‐substituted β‐CDs. The stabilities of the camptothecin complexes obtained from solubility measurements of five of the nine CD derivatives were significantly higher than for any other CD derivative known from literature. The remaining four CD derivatives were insoluble in water. In addition, corresponding mono‐substituted CD derivatives were synthesized that also showed improved binding constants. Among them the 9‐H‐purine derivative was the best, being comparable to the investigated hepta‐substituted β‐CDs. Since the measured binding free energies correlated satisfactorily with the calculated scores, the applied scoring functions appeared to be appropriate for the selection of promising candidates for receptor synthesis.