Investigation of structural requirements of anticancer activity at the paclitaxel/tubulin binding site using CoMFA and CoMSIA

Islam, Nazrul, Song, Yuqing, & Iskander, Magdy (2003) Investigation of structural requirements of anticancer activity at the paclitaxel/tubulin binding site using CoMFA and CoMSIA. Journal of Molecular Graphics & Modelling, 21(4), pp. 263-272.

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Abstract

CoMFA and CoMSIA analysis were utilized in this investigation to define the important interacting regions in paclitaxel/tubulin binding site and to develop selective paclitaxel-like active compounds. The starting geometry of paclitaxel analogs was taken from the crystal structure of docetaxel. A total of 28 derivatives of paclitaxel were divided into two groups—a training set comprising of 19 compounds and a test set comprising of nine compounds. They were constructed and geometrically optimized using SYBYL v6.6. CoMFA studies provided a good predictability (q2 = 0.699, r2 = 0.991, PC = 6, S.E.E. = 0.343 and F = 185.910). They showed the steric and electrostatic properties as the major interacting forces whilst the lipophilic property contribution was a minor factor for recognition forces of the binding site. These results were in agreement with the experimental data of the binding activities of these compounds. Five fields in CoMSIA analysis (steric, electrostatic, hydrophobic, hydrogen-bond acceptor and donor properties) were considered contributors in the ligand–receptor interactions. The results obtained from the CoMSIA studies were: q2 = 0.535, r2 = 0.983, PC = 5, S.E.E. = 0.452 and F = 127.884. The data obtained from both CoMFA and CoMSIA studies were interpreted with respect to the paclitaxel/tubulin binding site. This intuitively suggested where the most significant anchoring points for binding affinity are located. This information could be used for the development of new compounds having paclitaxel-like activity with new chemical entities to overcome the existing pharmaceutical barriers and the economical problem associated with the synthesis of the paclitaxel analogs. These will boost the wide use of this useful class of compounds, i.e. in brain tumors as the most of the present active compounds have poor blood–brain barrier crossing ratios and also, various tubulin isotypes has shown resistance to taxanes and other antimitotic agents.

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ID Code: 84531
Item Type: Journal Article
Refereed: Yes
Keywords: Anticancer agents, CoMFA, Paclitaxel, Paclitaxel analogs, Cancer chemotherapy, CoMSIA, Microtubules, Paclitaxel binding site
DOI: 10.1016/S1093-3263(02)00162-6
ISSN: 1873-4243 (online) 1093-3263 (print)
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PHARMACOLOGY AND PHARMACEUTICAL SCIENCES (111500)
Divisions: Current > Schools > School of Clinical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 26 May 2015 23:03
Last Modified: 26 May 2015 23:05

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