New insight into the action of tryptanthrins against Plasmodium falciparum: Pharmacophore identification via a novel submolecular QSAR descriptor

Abstract

A new submolecular quantitative structure activity relationship (QSAR) descriptor was applied toward elucidating the anti-malarial pharmacophore of tryptanthrins, a class of compounds known for their anti-parasitic activities. The new descriptor is based on experimental and computational measurements of the tunneling barriers of individual lobes of the molecular orbitals. Lobe-by-lobe QSAR correlation plots revealed a single lobe of the LUMO to be strongly associated with tryptanthrin’s anti-malarial activity. The correlation also showed a threshold behavior wherein barriers below a particular value show low IC50 values. Above the threshold, the correlation of IC50 vs the logarithm of the barrier is linear with R2 = 0.999. This barrier threshold may be applied as a design criterion for future tryptanthrin-based anti-malarial lead optimization. The new descriptor may be broadly applicable toward other molecular systems of interest, such as catalysts, pesticides, and herbicides. The authors have named the new descriptor: submolecular tunneling analysis of barriers (STAB).