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In silico inspired design and synthesis of a novel tubulin-binding anti-cancer drug: folate conjugated noscapine (Targetin)

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Title In silico inspired design and synthesis of a novel tubulin-binding anti-cancer drug: folate conjugated noscapine (Targetin)
 
Creator NAIK, PK
LOPUS, M
ANEJA, R
VANGAPANDU, SN
JOSHI, HC
 
Subject Noscapine
Targetin
Folate-noscapine
Free energy of binding
Tubulin binding affinity
Microtubule dynamics
Anti-cancer activity
MICROTUBULE DYNAMIC INSTABILITY
OVARIAN-CANCER
CELL-PROLIFERATION
ACCURATE DOCKING
PERTURB MITOSIS
NORMAL-TISSUES
COLCHICINE
AFFINITY
AGENT
PHARMACOKINETICS
 
Description Our screen for tubulin-binding small molecules that do not depolymerize bulk cellular microtubules, but based upon structural features of well known microtubule-depolymerizing colchicine and podophyllotoxin, revealed tubulin binding anti-cancer property of noscapine (Ye et al. in Proc Natl Acad Sci USA 95:2280-2286, 1998). Guided by molecular modelling calculations and structure-activity relationships we conjugated at C9 of noscapine, a folate group-a ligand for cellular folate receptor alpha (FR alpha). FR alpha is over-expressed on some solid tumours such as ovarian epithelial cancers. Molecular docking experiments predicted that a folate conjugated noscapine (Targetin) accommodated well inside the binding cavity (docking score -11.295 kcal/mol) at the interface between alpha- and beta-tubulin. The bulky folate moiety of Targetin is extended toward lumen of microtubules. The binding free energy (Delta G (bind)) computed based on molecular mechanics energy minimization was -221.01 kcal/mol that revealed favourable interaction of Targetin with the receptor. Chemical synthesis, tubulin-binding experiments, and anti-cancer activity in vitro corroborate fully well with the molecular modelling experiments. Targetin binds tubulin with a dissociation constant (K (d) value) of 149 +/- A 3.0 mu M and decreases the transition frequencies between growth and shortening phases of microtubule assembly dynamics at concentrations that do not alter the total polymer mass. Cancer cells in general were more sensitive to Targetin compared with the founding compound noscapine (IC50 in the range of 15-40 mu M). Quite strikingly, ovarian cancer cells (SKOV3 and A2780), known to overexpress FR alpha, were much more sensitive to targetin (IC50 in the range of 0.3-1.5 mu M).
 
Publisher SPRINGER
 
Date 2014-10-15T14:26:01Z
2014-10-15T14:26:01Z
2012
 
Type Article
 
Identifier JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 26(2)233-247
http://dx.doi.org/10.1007/s10822-011-9508-z
http://dspace.library.iitb.ac.in/jspui/handle/100/15098
 
Language en