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bioRxiv · 10.1101/2021.06.24.449800

Characterization of novel competitive inhibitors of P. falciparum cGMP-dependent protein kinase

Eck, T.·Laureano de Souza, M.·Bheemanoboina, R. R. Y.·Chakrasali, R.·Kreiss, T.·Siekierka, J. J.·Rotella, D. P.·Bhanot, P.·Goodey, N. M.
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Abstract

P. falciparum cGMP-dependent protein kinase (PfPKG) is an enticing anti-malarial drug target. Structurally novel isoxazole-based compounds were shown to be ATP competitive inhibitors of PfPKG. Isoxazoles 3 and 5 had Ki values of 0.7 {+/-} 0.2 and 2.3 {+/-} 0.9 nM, respectively, that are comparable to a known standard, 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H pyrrol-3-yl] pyridine (1.4 {+/-} 0.5 nM). They also exhibited excellent selectivity for PfPKG over the human ortholog and the gatekeeper mutant T618Q PfPKG, which mimics the less accessible binding site of the human ortholog. The human orthologs larger binding site volume was predicted to explain the selectivity of the inhibitors for the P. falciparum enzyme. Analogs 4 and 6 were at least 20-fold less potent compared to 3 and 5, suggesting that removing the carbonyl group in 3 or altering the diethylamino moiety in 5 reduced affinity.

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Eck, T., Laureano de Souza, M., Bheemanoboina, R. R. Y., Chakrasali, R., Kreiss, T., Siekierka, J. J., Rotella, D. P., Bhanot, P., Goodey, N. M.. 2021-06-24. Characterization of novel competitive inhibitors of P. falciparum cGMP-dependent protein kinase. https://doi.org/10.1101/2021.06.24.449800

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