Successful in silico discovery of natural inhibitors for human rhinovirus coat protein

Human rhinoviruses (HRVs) are the major cause of mild respiratory diseases generally known as the common cold. These illnesses still lack effective antiviral treatment. A promising strategy deals with the inhibition of the structurally identified HRV coat protein, thus blocking the uncoating of the viral particles and preventing cell attachment [1].

Based on this target information, the aim of this study was to apply an in silico approach to (i) identify virtually active ligands from nature, (ii) detect promising antiviral herbal products, and (iii) validate this strategy by the isolation and experimental investigation of the predicted virtual hits. A recently generated pharmacophore model [2] was used to virtually screen our in-house generated database DIOS consisting of >9 000 natural products [3]. Different sesquiterpene coumarins from asafetida revealed as virtual hits from the screening filtering experiment with Catalyst (Vers. 4.11). Four sesquiterpene umbelliferone ethers were isolated and identified as microlobiden, kellerine, farnesiferol B and C by 1D and 2D NMR experiments. Their antiviral activity has been determined in cytopathic effect inhibitory assays [4] with different picornavirus species. All compounds were tested using noncytotoxic sample concentrations. Results were compared with the capsid-binding activity of pleconaril. The virtual hits farnesiferol B and C showed selective inhibitory effects against pleconaril-sensitive HRV-2 with IC₅₀ of 1.25 (0.10–4.26; CI₉₅) µM and 3.79 (2.46–8.23; CI₉₅) µM, respectively. By contrast, microlobiden and kellerine, which did not map with the pharmacophore's features, showed no antiviral potential. The correlation of experimental results with virtually predicted activities obtained from this study underlines the power of the virtual screening approach for the rational discovery of bioactive natural products [5].

Acknowledgements: This work was granted by the 'Nachwuchsförderung 2005' of the LFU Innsbruck (J.M.R.).

References: [1] Hadfield, A.T. et al. (1999) Proc Natl Acad Sci USA 96: 14730–5. [2] Steindl, T.M. et al. (2005) J Med Chem 48: 6250–60. [3] Rollinger, J.M. et al. (2004) J Chem Inf Comput Sci 44: 480–8. [4] Schmidtke M. et al. (2001) J Virol Meth 95: 133–43. [5] Rollinger, J.M. et al. (2006) Planta Med. 72: 671–8.