Molecular modelling studies of benzofuranoid neolignan analogues as potential tubulin antagonists and anti-leishmanial agents

Leishmaniasis, a group of tropical diseases caused by parasites of the genus Leishmania, attracts considerable research efforts world-wide. Only few treatments for the various forms of the disease are available so that the search for new drugs remains a challenge. In this regard, computational drug discovery programs towards particular leishmanial targets are a promising approach. Several such targets have been proposed and studied, one of which is the parasite's tubulin which differs from mammalian tubulin [1]. In previous studies it was shown that dihydrobenzofuranoid neolignan analogues of the general structure 1 are antagonists of tubulin polymerization [2] and some derivatives have already been demonstrated to be selectively toxic against Leishmania donovani [3].

The current research aims at a rational design of antileishmanial neolignans through ligand-based virtual screening. To this end, a quantitative structure-activity relationship (QSAR) study on a series of neolignan analogues with variable antileishmanial activity and cytotoxicity against mammalian cells³ was carried out using Open3DQSAR [4].

The best QSAR model for antileishmanial activity was characterized by the following parameters: R²= 0.990 (n = 15, 4LV); Q²= 0.766; P²= 0.909 (n = 5). The reasonably good statistical quality of this model and a complementary model for cytotoxicity allowed activity and selectivity predictions for new, yet untested, structures. Based on these models, high antileishmanial activity and selectivity was predicted for several derivatives (e.g. 2-4), whose synthesis and biological testing is in progress. Docking simulations targeting the parasitic tubulin were also carried out. Nevertheless, no correlation with the former results was observed.

In conclusion, new potentially active and selective neolignan derivatives were designed based on 3D-QSAR modelling. Further studies to achieve a comprehensive knowledge of their mode of action as well as in vitro biological testing are still required.

Acknowledgements: F. Bernal was supported by the Departamento Administrativo de Ciencia, Tecnología e Innovación (Colombia), COLCIENCIAS, with the scholarship No. 679. This project is an activity within the Research Network Natural Products against Neglected Diseases (ResNet NPND; http://www.resnetnpnd.org/).

Keywords: Dihydrobenzofuran neolignans, tubulin, molecular modelling, Leishmania.

References:

[1] Fennell BJ, Naughton JA, Barlow J, Brennan G, Fairweather I, Hoey E, McFerran N, Trudgett A, Bell A. Microtubules as antiparasitic drug targets. Expert Opin Drug Discov 2008; 3: 501 – 518

[2] Pieters L, Van Dyck S, Gao M, Bai R, Hamel E, Vlietinck A, Lemière G. Synthesis and biological evaluation of dihydrobenzofuran lignans and related compounds as potential antitumor agents that inhibit tubulin polymerization. J Med Chem 1999; 42: 5475 – 5481

[3] Van Miert S, Van Dyck S, Schmidt TJ, Brun R, Vlietinck A, Lemière G, Pieters L. Antileishmanial activity, cytotoxicity and QSAR analysis of synthetic dihydrobenzofuran lignans and related benzofurans. Bioorg Med Chem 2005; 13: 661 – 669

[4] Tosco P, Balle T. Open3DQSAR: a new open-source software aimed at high-throughput chemometric analysis of molecular interaction fields. J Mol Model 2011; 17: 201 – 208