title: Rational design, synthesis and biological evaluations of amino-noscapine: a high affinity tubulin-binding noscapinoid.
abstract: Noscapine and its derivatives are important microtubule-interfering agents shown to have potent anti-tumor activity. The binding free energies (ΔG (bind)) of noscapinoids computed using linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model were in agreement with the experimental ΔG (bind) with average root mean square error of 0.082 kcal/mol. This LIE-SGB model guided us in designing a novel derivative of noscapine, amino-noscapine [(S)-3-((R)-9-amino-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1, 3] dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxy isobenzo-furan-1(3H)-one] that has higher tubulin binding activity (predicted ΔG (bind) = -6.438 kcal/mol and experimental ΔG (bind) = -6.628 kcal/mol) than noscapine, but does not significantly change the total extent of the tubulin subunit/polymer ratio. The modes of interaction of amino-noscapine with the binding pocket of tubulin involved three hydrogen bonds and are distinct compared to noscapine which involved only one hydrogen bond. Also the patterns of non-bonded interactions are albeit different between both the lignads. The 'blind docking' approach (docking of ligand with different binding sites of a protein and their evaluations) as well as the reasonable accuracy of calculating ΔG (bind) using LIE-SGB model constitutes the first evidence that this class of compounds binds to tubulin at a site overlapping with colchicine-binding site or close to it. Our results revealed that amino-noscapine has better anti-tumor activity than noscapine.
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. pnaik2@emory.edu
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Naik
authors.forename: Biswa Prasun
authors.initials: BP
authors.lastname: Chatterji
authors.forename: Surya N
authors.initials: SN
authors.lastname: Vangapandu
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
authors.forename: Ramesh
authors.initials: R
authors.lastname: Chandra
authors.forename: Srinivas
authors.initials: S
authors.lastname: Kanteveri
authors.forename: Harish C
authors.initials: HC
authors.lastname: Joshi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D000996:Antitussive Agents; D001665:Binding Sites; D003078:Colchicine / Q000737:chemistry*; D015195:Drug Design; D006860:Hydrogen Bonding; D008024:Ligands; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009665:Noscapine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D058105:Polymerization; D011485:Protein Binding; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism
chemical_list: C561203:9-amino-alpha-noscapine; D000970:Antineoplastic Agents; D000996:Antitussive Agents; D008024:Ligands; D014404:Tubulin; D009665:Noscapine; D003078:Colchicine