Computational approaches towards the discovery and optimisation of cruzain inhibitors

Santos, Viviane Corrêa; Ferreira, Rafaela Salgado

doi:10.1590/0074-02760210385

Cited by 8 publications

(3 citation statements)

References 15 publications

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“…It is possible to verify that its 8-methoxy-substituted coumarin nucleus is found at the S2 subpocket entry since it has a preference for van der Waals interactions with hydrophobic substituents, [74][75][76] while its thiosemicarbazone moiety is oriented toward the shallow S1 subpocket, which is typically associated with inhibitors and better accommodates non-bulky groups. 77,78 It may explain the better activity of FN-27 towards CRZ in our experimental assays. Additionally, it was observed that despite the nucleophilic Cys 25 residue being found near the methylamine double bond of FN-27 (a potential electrophilic moiety at a distance of 4.02 Å), it probably did not undergo covalent bonding, although an anion-p interaction could be possible for it.…”

Section: 5mentioning

confidence: 82%

Coumarin-based derivatives targetingTrypanosoma cruzicruzain andTrypanosoma bruceicathepsin L-like proteases

Nunes

Silva

et al. 2023

New J. Chem.

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Section: 5mentioning

confidence: 82%

Coumarin-based derivatives targetingTrypanosoma cruzicruzain andTrypanosoma bruceicathepsin L-like proteases

Nunes

Silva

et al. 2023

New J. Chem.

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“…Among the validated targets, cruzain, the main cysteine protease of T. cruzi, is one of the most well-studied. , Cruzain is relevant to the parasite life cycle, replication, immune response, and virulence − and has been established as a validated target for trypanocidal compounds. − Among the several compound classes reported as cruzain inhibitors, − covalent inhibitors are especially interesting, given the overall potency and residence time provided by the covalent bond . The general mechanism of covalent inhibition of a protein by a small molecule (Figure ) starts with the formation of a reversible, low-affinity pre-covalent complex (E···I), which is governed by noncovalent interactions.…”

Section: Introductionmentioning

confidence: 99%

“…Among the validated targets, cruzain, the main cysteine protease of T. cruzi, is one of the most well-studied. 6,7 Cruzain is relevant to the parasite life cycle, replication, immune response, and virulence 8−10 and has been established as a validated target for trypanocidal compounds. 11−14 Among the several compound classes reported as cruzain inhibitors, 15−26 covalent inhibitors are especially interesting, given the overall potency and residence time provided by the covalent bond.…”

Section: ■ Introductionmentioning

confidence: 99%

Experimental and Computational Study of Aryl-thiosemicarbazones Inhibiting Cruzain Reveals Reversible Inhibition and a Stepwise Mechanism

Martins

Oliveira

Lameira

et al. 2023

J. Chem. Inf. Model.

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Trypanosoma cruzi is a parasite that infects about 6–7 million people worldwide, mostly in Latin America, causing Chagas disease. Cruzain, the main cysteine protease of T. cruzi, is a validated target for developing drug candidates for Chagas disease. Thiosemicarbazones are one of the most relevant warheads used in covalent inhibitors targeting cruzain. Despite its relevance, the mechanism of inhibition of cruzain by thiosemicarbazones is unknown. Here, we combined experiments and simulations to unveil the covalent inhibition mechanism of cruzain by a thiosemicarbazone-based inhibitor (compound 1). Additionally, we studied a semicarbazone (compound 2), which is structurally similar to compound 1 but does not inhibit cruzain. Assays confirmed the reversibility of inhibition by compound 1 and suggested a two-step mechanism of inhibition. The K i was estimated to be 36.3 μM and K i* to be 11.5 μM, suggesting the pre-covalent complex to be relevant for inhibition. Molecular dynamics simulations of compounds 1 and 2 with cruzain were used to propose putative binding modes for the ligands. One-dimensional (1D) quantum mechanics/molecular mechanics (QM/MM) potential of mean force (PMF) and gas-phase energies showed that the attack of Cys25-S– on the CS or CO bond yields a more stable intermediate than the attack on the CN bond of the thiosemicarbazone/semicarbazone. Two-dimensional (2D) QM/MM PMF revealed a putative reaction mechanism for compound 1, involving the proton transfer to the ligand, followed by the Cys25-S– attack at CS. The ΔG and energy barrier were estimated to be −1.4 and 11.7 kcal/mol, respectively. Overall, our results shed light on the inhibition mechanism of cruzain by thiosemicarbazones.

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Environmental, industrial, and health benefits of Moringa oleifera

Mahaveerchand,

Abdul Salam

2024

Phytochem Rev

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The rise of air, water, and soil pollution poses a significant threat to global health, leading to widespread disease and premature mortality. Soil health is vital, ensuring the production of safe food, but it is compromised by pollutants such as heavy metals, pesticides, plastics, and excessive fertilization, resulting in the depletion of beneficial microorganisms and subsequently groundwater contamination. Water bodies are polluted due to contamination from industrial effluents, domestic wastewater, agricultural runoff, and oil spillage, further intensifying environmental pollution. On the other hand, atmospheric pollution, characterized by high emissions of gases, volatile compounds, greenhouse gases, not only impacts the climate but also poses serious risks to human health, leading to respiratory diseases, cardiovascular issues, and increased cancer risks. Thus, the strategic utilization of traditional plants emerges as a potent tool for environmental restoration and improving human health. The plants possess natural filtering capabilities, absorbing pollutants from air, soil, and water, thus mitigating their adverse effects. Through phytoremediation, plants can be actively used to extract and remove contaminants, contributing to detoxification and improving water and soil quality. Additionally, plants offer various health benefits. Moringa oleifera or the drumstick plant belonging to the Moringaceae family is one such indigenous plant with wide applications, that can be grown in extreme arid conditions. Since ancient times, this plant has been used for treating skin infections, anaemia, and blood impurities. This plant thrives in diverse climates addressing over 300 different aliments. Rich in phytochemicals and bioactive compounds, M. oleifera serve as a superfood, offering high nutritional values and exhibiting potential for drug development with fewer side effects. Extensive research has elucidated the diverse properties and applications of M. oleifera, however, in-depth research is needed to identify bioactive molecules, phytochemicals, and protein compounds involved, which will aid in understanding of the mechanisms of action of the plant's diverse functions. Although studies have reported several of individual M. oleifera attributes, there is no comprehensive study available addressing its diverse applications. This review covers the findings of past three decades and provides a detailed outline of M. oleifera plant and its various parts, its applications in environmental, industrial, food and health aspects documented to date.

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Computational approaches towards the discovery and optimisation of cruzain inhibitors

Cited by 8 publications

References 15 publications

Coumarin-based derivatives targetingTrypanosoma cruzicruzain andTrypanosoma bruceicathepsin L-like proteases

Coumarin-based derivatives targetingTrypanosoma cruzicruzain andTrypanosoma bruceicathepsin L-like proteases

Experimental and Computational Study of Aryl-thiosemicarbazones Inhibiting Cruzain Reveals Reversible Inhibition and a Stepwise Mechanism

Environmental, industrial, and health benefits of Moringa oleifera

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