Investigation of the reactivity indices for the formation of substituted dinitroanilines and correlations to their dockings on α-tubulin of Plasmodium falciparum

Udofia, Inemesit A.; Ogunbayo, Taofeek B.; Oloba-Whenu, Oluwakemi A.; Isanbor, Chukwuemeka; Ramasami, Ponnadurai

doi:10.1007/s00894-019-4169-2

Cited by 1 publication

(1 citation statement)

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“…Based on the OR mutation data and computational results, several research groups have proposed different ORY binding sites (ORYbs) in α-tubulin of plants and protozoan parasites. Some of these groups have suggested that dinitroaniline herbicides could bind directly behind the α-tubulin N-loop (H1–S2 loop, amino acids 29–64) or close to the L-loop (S9–S10 loop, amino acids 356–373). ,− Meanwhile, other studies have proposed that ORYbs might be located on top of the N-loop near to the β-tubulin interface (see Figure D). − Unfortunately, these proposed binding sites are found in poorly accessible regions, away from amino acids with known OR mutations or comprise several highly conserved residues between ORY-susceptible and non-susceptible organisms.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the Possible Oryzalin-Binding Site in the α-Tubulin of Toxoplasma gondii

Aguayo‐Ortiz

Domı́nguez

2022

ACS Omega

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Dinitroaniline derivatives have been widely used as herbicidal agents to control weeds and grass. Previous studies demonstrated that these compounds also exhibit good antiparasitic activity against some protozoan parasites. Oryzalin (ORY), a representative dinitroaniline derivative, exerts its antiprotozoal activity against Toxoplasma gondii by inhibiting the microtubule polymerization process. Moreover, the identification of ORY-resistant T. gondii lines obtained by chemical mutagenesis confirmed that this compound binds selectively to α-tubulin. Based on experimental information reported so far and a multiple sequence analysis carried out in this work, we propose that the pironetin (PIR) site is the potential ORY-binding site. Therefore, we employed state-of-the-art computational approaches to characterize the interaction profile of ORY at the proposed site in the α-tubulin of T. gondii . An exhaustive search for other possible binding sites was performed using the Wrap “N” Shake method, which showed that ORY exhibits highest stability and affinity for the PIR site. Moreover, our molecular dynamics simulations revealed that the dipropylamine substituent of ORY interacts with a hydrophobic pocket, while the sulfonamide group formed hydrogen bonds with water molecules at the site entrance. Overall, our results suggest that ORY binds to the PIR site on the α-tubulin of the protozoan parasite T. gondii . This information will be very useful for designing less toxic and more potent antiprotozoal agents.

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