A novel antiplasmodial compound: integration of<i>in silico</i>and<i>in vitro</i>assays

Júnior, David Bacelar Costa; Araújo, Janay Stefany Carneiro; Oliveira, Larissa de Mattos; Neri, Flávio Simas Moreira; Moreira, Paulo Otávio Lourenço; Taranto, Alex Gutterres; Fonseca, Amanda Luisa da; Varotti, Fernando de Pilla; Leite, Franco Henrique Andrade

doi:10.1080/07391102.2021.1882339

Cited by 3 publications

(7 citation statements)

References 59 publications

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“…The interactions between TCL and CHJ primarily involve essential hydrogen bonding interactions with Tyr277 and the cofactor NAD + , accompanied by additional electrostatic interactions such as pi-cation interactions with NAD + . Both ligands also engage in hydrophobic interactions, contributing to their binding affinity. ,, In contrast, distinct interaction patterns were observed when the interactions of lead compounds LD1 and LD2 with the reference ligands TCL and CHJ at the PfENR binding site. In this case, LD1 and LD2 exhibited different predominant interactions, particularly in hydrogen bonding and electrostatic interactions, compared with the standard ligands TCL and CHJ.…”

Section: Resultsmentioning

confidence: 98%

“…To investigate the triclosan derivatives and their potential as inhibitors of PfENR, Library 1 was constructed by extensively reviewing four seminal publications that focused on modifying the triclosan scaffold with various substituents. − These modifications introduced diverse functional groups, including nitrile, hydroxyl, amide derivatives, aniline, and others, thereby expanding the chemical versatility of the triclosan core. This strategy of exploring compounds with similar but untested structures based on molecules previously evaluated against a specific target is a standard approach in this field. ,, The complete list of selected compounds in Library 1 can be found in Table S1.…”

Section: Resultsmentioning

confidence: 99%

“…This strategy of exploring compounds with similar but untested structures based on molecules previously evaluated against a specific target is a standard approach in this field. 40 , 60 , 61 The complete list of selected compounds in Library 1 can be found in Table S1 .…”

Section: Resultsmentioning

confidence: 99%

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Exploring Novel Antimalarial Compounds Targeting Plasmodium falciparum Enoyl-ACP Reductase: Computational and Experimental Insights

A R Oliveira,

G D V Morales,

M O Sousa

et al. 2024

ACS Omega

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Malaria, caused by Plasmodium protozoa with Plasmodium falciparum as the most virulent species, continues to pose significant health challenges. Despite the availability of effective antimalarial drugs, the emergence of resistance has heightened the urgency for developing novel therapeutic compounds. In this study, we investigated the enoyl-ACP reductase enzyme of P. falciparum (PfENR) as a promising target for antimalarial drug discovery. Through a comprehensive analysis, we conducted a comparative evaluation of two lead compounds, LD1 (CID: 44405336, lead compounds 1) and LD2 (CID: 72703246, lead compounds 2), obtained from the PubChem/NCBI ligand database, to serve as reference molecules in the identification of potential derivatives using virtual screening assays. Among the newly identified candidates, Ligand 1 (LG1) and Ligand 2 (LG2) exhibited intriguing characteristics and underwent further investigation through docking and molecular dynamics simulations. Ligand 1 (LG1) demonstrated interactions similar to LD1, including hydrogen bonding with Asp218, while Ligand 2 (LG2) displayed superior binding energy comparable to LD1 and LD2, despite lacking hydrogen bonding interactions observed in the control compounds triclosan and its derivative 7-(4-chloro-2-hydroxyphenoxy)-4-methyl-2H-chromen-2-one (CHJ). Following computational validation using the MM/GBSA method to estimate binding free energy, commercially acquired LG1 and LG2 ligands were subjected to in vitro testing. Inhibition assays were performed to evaluate their potential as PfENR inhibitors alongside triclosan as a control compound. LG1 exhibited no inhibitory effects, while LG2 demonstrated inhibitory effects like triclosan. In conclusion, this study contributes valuable insights into developing novel antimalarial drugs by identifying LG2 as a potential ligand and employing a comprehensive approach integrating computational and experimental methodologies.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

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Exploring Novel Antimalarial Compounds Targeting Plasmodium falciparum Enoyl-ACP Reductase: Computational and Experimental Insights

A R Oliveira,

G D V Morales,

M O Sousa

et al. 2024

ACS Omega

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“…The AH5 has a benzene ring in the R-substituent of the compound and might cause less binding energy and high inhibitory activity of plasmodial targeted protein [ 41 ]. A recent study reported that 10,977 molecules were selected based on the pharmacophore models and performed inhibitory activity against the PfENR protein [ 42 ]. Nine hybrid compounds of 7-substituted 4-aminoquinoline and cinnamic acid were also reported as a novel derivative compounds to inhibit the Pf3D7 chloroquine-sensitive strain.…”

Section: Discussionmentioning

confidence: 99%

“…The phosphodianion was exposed at the residue Pro202–Val220, while the pyrimidine gripper of PfOMPDC was mapped at Ala151–Thr165. Interestingly, the active sites of pyrimidine were dominantly identified on the active sites of triterpene glycoside [ 42 , 43 ]. Previous studies also reviewed and investigated that several natural products showed effectiveness as targeted for parasites.…”

Section: Discussionmentioning

confidence: 99%

In Silico Approach Triterpene Glycoside of H. atra Targeting Orotidine 5-Monophosphate Decarboxylase Protein (PfOMPDC) in P. falciparum Infection Mechanism

Utami,

Setianingsih,

Sari

2024

BioMed Research International

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This study accessed the potential antimalarial activity of triterpene glycoside of H. atra through targeting orotidine 5-monophosphate decarboxylase protein (PfOMPDC) in P. falciparum by molecular docking. Nine triterpene glycosides from H. atra extract modeled the structure by the Corina web server and interacted with PfOMPDC protein by using Hex 8.0.0. The docking results were visualized and analyzed by Discovery Studio version 21.1.1. 17-Hydroxyfuscocineroside B showed the lowest binding energy in PfOMPDC interaction, which was -1,098.13 kJ/mol. Holothurin A3, echinoside A, and fuscocineroside C showed low binding energy. Nine triterpene glycosides of H. atra performed interaction with PfOMPDC protein at the same region. Holothurin A1 posed interaction with PfOMPDC protein by 8 hydrogen bonds, 3 hydrophobic interactions, and 8 unfavorable bonds. Several residues were detected in the same active sites of other triterpene glycosides. Residue TYR111 was identified in all triterpene glycoside complexes, except holothurin A3 and calcigeroside B. In summary, the triterpene glycoside of H. atra is potentially a drug candidate for malaria therapeutic agents. In vitro and in vivo studies were required for further investigation.

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Proposition of In silico Pharmacophore Models for Malaria: A Review

de Sousa,

de Araújo,

Rodrigues

et al. 2024

CCHTS

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In the field of medicinal chemistry, the concept of pharmacophore refers to the specific region of a molecule that possesses essential structural and chemical characteristics for binding to a receptor and eliciting biological activity. Understanding the pharmacophore is crucial for drug research and development, as it allows the design of new drugs. Malaria, a widespread disease, is commonly treated with chloroquine and artemisinin, but the emergence of parasite resistance limits their effectiveness. This study aims to explore computer simulations to discover a specific pharmacophore for Malaria, providing new alternatives for its treatment. A literature review was conducted, encompassing articles proposing a pharmacophore for Malaria, gathered from the "Web of Science" database, with a focus on recent publications to ensure up-to-date analysis. The selected articles employed diverse methods, including ligand-based and structurebased approaches, integrating molecular structure and biological activity data to yield comprehensive analyses. Affinity evaluation between the proposed pharmacophore and the target receptor involved calculating free energy to quantify their interaction. Multiple linear regression was commonly utilized, though it is sensitive to multicollinearity issues. Another recurrent methodology was the use of the Schrödinger package, employing tools such as the Phase module and the OPLS force field for interaction analysis. Pharmacophore model proposition allows threedimensional representations guiding the synthesis and design of new biologically active compounds, offering a promising avenue for discovering therapeutic agents to combat Malaria.

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A novel antiplasmodial compound: integration ofin silicoandin vitroassays

Cited by 3 publications

References 59 publications

Exploring Novel Antimalarial Compounds Targeting Plasmodium falciparum Enoyl-ACP Reductase: Computational and Experimental Insights

Exploring Novel Antimalarial Compounds Targeting Plasmodium falciparum Enoyl-ACP Reductase: Computational and Experimental Insights

In Silico Approach Triterpene Glycoside of H. atra Targeting Orotidine 5-Monophosphate Decarboxylase Protein (PfOMPDC) in P. falciparum Infection Mechanism

Proposition of In silico Pharmacophore Models for Malaria: A Review

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