Development of robust QSAR model using rapid overlay of crystal structures (ROCS) based alignment: a test case of Tubulin inhibitors

作者：Uddin Reaz^*; Naz Afshan; Akhtar Nahid; ul Haq Zaheer

来源：Medicinal Chemistry Research, 2013, 22(7): 3229-3241.

DOI：10.1007/s00044-012-0327-0

• 3D-QSAR
• Tubulin inhibitors
• Genetic algorithm
• CoMFA
• CoMSIA

Conformational alignment is the most important step in 3D-QSAR methodology. There are various methods available to create an alignment hypothesis for the compounds being studied in 3D-QSAR. Most famous alignment methods include: alignment on a suitable template conformation, field fit alignment, database alignment, pharmacophore-based alignment, atom fit, and docking based alignment. All of the above-mentioned methods were explored previously to sample the conformational space in 3D-QSAR. Current study is dealing with the situation where most of the alignment methods were failed to produce a statistically robust 3D-QSAR model. Therefore, a relatively new alignment scheme was employed using ROCS (Rapid Overlay of Chemical Structures) method from OpenEyes. In the present study, Combretastatin A-4 based Tubulin inhibitors were used as case study. Co-crystal ligand conformation (i.e., Colchicine) in the Tubulin complex structure (PDB ID: 1SA0) was utilized as a template molecule. To date, very few applications of ROCS-based alignments in 3D-QSAR are reported in literature. Therefore, current study will serve as an addition to the existing status of using ROCS in 3D-QSAR. Genetic algorithm was utilized to build final 3D-QSAR model. Correlation obtained from final model suggesting that robust 3D-QSAR model was constructed.

• 出版日期2013-7