Abstract 97: In silico computational modeling and virtual screening of novel noscapinoid library as potent microtubule interacting anticancer drugs

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Tubulin remains a persistent and promising target for anti-cancer therapy. This is well validated by the already approved clinically used drug classes such as taxoids and vincas. We have previously discovered a new class of anti-microtubule (MT) drugs, noscapinoids. The lead compound, noscapine, is an orally available anti-cough plant alkaloid that binds tubulin and makes MTs less dynamic. Using computational algorithms such as Glide Extra Precision, Quantum Polarized Ligand Docking (QPLD), Molecular Mechanics Generalized Born Surface Area (MM-GB/SA), EmBrace and Solvation Generalized Born-Linear Interaction Energy (SGB-LIE), we have generated molecular models of noscapine-tubulin complex. Furthermore, based upon structure-function analyses of noscapine, we have identified a key residue on the isoquinoline ring of noscapine that can be modified without losing its biological activity. We report a library of novel derivatives, based upon combinatorial in silico approaches that can be chemically synthesized and tested in vitro and in vivo in animal models of human tumor xenografts in immune compromised mice. The prototype analogs synthesized so far have non-toxic to normally dividing healthy tissues but pro-apoptotic in a wide variety of cancer cells in vitro and in vivo. Some of these prototypes have shown already that these approaches can generate compounds more effective than the lead compound. Unlike currently available clinical anticancer MT-drugs, noscapine and its derivatives are orally available, and display no toxicities such as myelosuppression and immunosuppression, peripheral neuropathies, or pathology of gastrointestinal tract. Moreover, noscapine readily crosses the blood brain barrier. The in silico libraries generated here promise to be even more effective. Additionally, because the mechanisms by which different anti-MT drugs induce apoptosis can vary widely in both, the same cell lineage as well as in distinct lineages, there is a tremendous opportunity for a better therapeutic outcome by combining noscapinoids with already approved MT-drugs in a cancer type specific manner. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 97.