The rational design of novel structures based on the Leiodermatolide scaffold capable of inhibiting Tubulin

Abstract

Referred to as the ‘silent killer’, pancreatic cancer has been ranked as the seventh primary cause of cancer-related deaths globally, with the highest incidence occurring in more developed countries. Despite advances in treatment, mortality rate remains high with a 9% 5 year survival rate (Rawla et al, 2019). Microtubules have been identified as excellent targets in tumour treatment since minor alterations in their dynamics can inhibit cell cycle progression inducing apoptosis. A polyketide molecule produced by the Leiodermatium sp. deep-water marine sponge, leiodermatolide, has shown anti-mitotic and cytotoxic activity against pancreatic cancer cells (Guzmán et al, 2016). Similar to other established microtubule targeting agents, leiodermatolide interacts with one of the three tubulin binding sites and alters microtubule dynamics through a novel mechanism. Therefore, the leiodermatolide scaffold was used in order to identify potentially useful tubulin antagonists. Crystallographic data for the three holo tubulin LBPs: 5J2T, 5LP6 and 1JFF and the critical interactions with their respective ligands were analysed in Sybyl®-X v2.1.1 (Tripos, 2013). Leiodermatolide was modelled and conformational analysis was carried out from which three optimal Lipinski rule compliant conformers at each tubulin LBPs respectively were obtained. Virtual Screening of the consensus pharmacophores generated in ZincPharmer® (Koes and Camacho, 2012) was done and the Lipinski rule-compliant hits were docked into the three protomols of each pocket which were modelled in Sybyl®-X v2.1.1 (Tripos, 2013) and results were filtered according to total binding score. Seeds were generated for the de novo design process, where growth was sustained at designated loci to obtain Lipinski-compliant in silico molecules. Further filtration and optimisation may identify an optimal tubulin antagonist which may prove to be suitable for the clinical management of pancreatic cancer.