Conformational Properties of the Chemotherapeutic Drug Analogue Epothilone A: How to Model a Flexible Protein Ligand Using Scarcely Available Experimental Data

Abstract

Epothilones are among the most potent chemotherapeutic drugs used for the treatment of cancer. Epothilone A (EpoA), a natural product, is a macrocyclic molecule containing 34 non-hydrogen atoms and a thiazole side chain. NMR studies of EpoA in aqueous solution, unbound as well as bound to αβ-tubulin, and unbound in dimethyl sulfoxide (DMSO) solution have delivered sets of nuclear Overhauser effect (NOE) atom–atom distance bounds, but no structures based on NMR data are present in structural data banks. X-ray diffraction of crystals has provided structures of EpoA unbound and bound to αβ-tubulin. Since both crystal structures derived from X-ray diffraction intensities do not completely satisfy the three available sets of NOE distance bounds for EpoA, molecular dynamics (MD) simulations have been employed to obtain conformational ensembles in aqueous and in DMSO solution that are compatible with the respective NOE data. It was found that EpoA displays a larger conformational variability in DMSO than in water and the two conformational ensembles show little overlap. Yet, they both provide conformational scaffolds that are energetically accessible at physiological temperature and pressure.

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“…52 Other MD works that appear in the special issue include that on NPC1 protein that is involved in Niemann Pick type C disease, 53 on meso-Diaminopimelate dehydrogenase (meso-DAPDH), an enzyme for one-step synthesis of D-amino acids from 2-keto acids 54 and that involving Epothilone A-tubulin interactions. 55 kinetics for a wild type enzyme and seven mutants. 54 MD reveals that these point mutations reduced the productive conformations by the newly formed or eliminated interactions between the residues and ligands.…”

“…Other MD works that appear in the special issue include that on NPC1 protein that is involved in Niemann Pick type C disease, on meso-Diaminopimelate dehydrogenase (meso-DAPDH), an enzyme for one-step synthesis of d -amino acids from 2-keto acids and that involving Epothilone A-tubulin interactions . Using a combination of molecular modeling, docking, and MD, Elghobashi-Meinhardt analyzes cholesterol binding sites and investigates the structural flexibility of specific domains of NPC1 at pH 5 and pH 7.…”

“…Dolenc and co-workers analyze the structure and dynamics of an important chemotherapeutic drug analogue, Epothilone A (EpoA). Exhaustive MD-based analysis of the existing crystallographic and NMR data in water and DMSO highlights and removes certain discrepancies between the known data and provide a rich model of the conformational behavior of EpoA bound to tubulin …”