Microtubule Targeted Pharmacophore Study of Cryptophycin Derivatives for Effective Treatment of Cancer

ABSTRACT

Background and Objectives: Worldwide in 21^st century cancer become the foremost cause of death and it is become the second leading cause of death also estimated that 1 in 6 deaths is due to cancer. Recently, cryptophycin is a microtubule agent has been used in the treatment of cancer. This study was aimed to develop a pharmacophore model for cryptophycin analogues of tubulin inhibitors by using quantitative approach to retrieve structurally diverse compounds with desired biological activity. Materials and Methods: Silicon graphics octane 2 R12000 computer running lrix 6.5.12 with Catalyst version 4.6 was used to generate pharmacophore models. A training set of 20 compounds and test set of 18 compounds were selected from the database was formed using HypoGen model based on the quantitative predictive character such as structural diversity and biological activity against human leukemia CCRF-CEM tumor cell lines. Results: A training set of 20 cryptophycin inhibitors exhibiting in vitro IC₅₀ values ranging from 0.04 nm to 2500 nm were utilized to generate a quantitative pharmacophore. The best pharmacophore hypothesis generation consists of one hydrogen bond acceptor, one hydrogen bond donor, one hydrophobic aliphatic and one ring aromatic as important features. The selected best pharmacophore hypothesis yielded a RMS deviation of 0.774 and a correlation coefficient of 0.948 with a cost difference of 57.71. Predicted accuracy value for the test set compounds were greater than 95%. Conclusion: The results of this study showed distinct chemical features useful in the design and development of inhibitors with greater selectivity towards tubulin.