Driving antimalarial design through understanding of target mechanism

Calic, Petar P. S.; Mansouri, Mahta; Scammells, Peter J.; McGowan, Sheena

doi:10.1042/bst20200224

Cited by 13 publications

(4 citation statements)

References 99 publications

(167 reference statements)

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“…π–π interactions are observed between the naphthyl portion and residues Phe227 and Phe188. These interactions are made possible because the naphthyl binding site allows the approximation of a pocket that arises from a considerable rotation of Phe188, denoting an interpretation that the Pf DHODH enzyme is capable of binding to several chemical classes with high affinity. , Mutations F188L and F188I show high-level resistance to Pf DHODH inhibitors, suggesting that the aromatic ring of phenylalanine forms more conducive interactions with inhibitors. In addition, Phe188 acts as a gate for docking in the pocket of the inhibitor binding site …”

Section: Resultsmentioning

confidence: 99%

“…Unconventional hydrogen interactions were observed with the three ligands DSM483 [iii(C16)O], DSM1- Pf DHODH [ii(N5)C], and DSM1- Pf DHODH(C276F) [i(C14)H], in addition to more alkyl interactions, alkyl with DSM483 [iii(C17)H] were analyzed. Val532 is part of a small hydrophobic channel also formed by Ile272 and Ile263. , The analysis of interactions between Pf DHODH and ligands showed that Val532 forms an important H binding with inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…Val532 is part of a small hydrophobic channel also formed by Ile272 and Ile263. 66,69 The analysis of interactions between Pf DHODH and ligands showed that Val532 forms an important H binding with 24 inhibitors.…”

Section: Dsm483 [I(c6)h] Dsm557 [I(c4)h] Dsm1[i(c15)n] and Dsm1-mentioning

confidence: 99%

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Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective

Lima Costa,

Bezerra,

de Lima Neto

et al. 2023

J. Phys. Chem. B

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Malaria is a parasitic disease that, in its most severe form, can even lead to death. Insect-resistant vectors, insufficiently effective vaccines, and drugs that cannot stop parasitic infestations are making the fight against the disease increasingly difficult. It is known that the enzyme dihydroorotate dehydrogenase (DHODH) is of paramount importance for the synthesis of pyrimidine from the Plasmodium precursor, that is, for its growth and reproduction. Therefore, its blockade can lead to disruption of the parasite's life cycle in the vertebrate host. In this scenario, Pf DHODH inhibitors have been considered candidates for a new therapy to stop the parasitic energy source. Given what is known, in this work, we applied molecular fractionation with conjugated caps (MFCC) in the framework of the quantum formalism of density functional theory (DFT) to evaluate the energies of the interactions between the enzyme and the different triazolopyrimidines (DSM483, DMS557, and DSM1), including a complex carrying the mutation C276F. From these results, it was possible to identify the main features of each system, focusing on the wild-type and mutant Pf DHODH and examining the major amino acid residues that are part of the four complexes. Our analysis provides new information that can be used to develop new drugs that could prove to be more effective alternatives to present antimalarial drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective

Lima Costa,

Bezerra,

de Lima Neto

et al. 2023

J. Phys. Chem. B

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“…Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (pfDHFR-TS) is a well-known homodimeric enzyme with DHFR and thymidylate synthase (TS) domain residues. pfDHFR-TS produces folates and thymidylate (dTMP), both of which are required for DNA synthesis, and has been studied extensively in order to develop effective antimalarial drugs [ 57 ].…”

Section: Methodsmentioning

confidence: 99%

DFT, ADMET and Molecular Docking Investigations for the Antimicrobial Activity of 6,6′-Diamino-1,1′,3,3′-tetramethyl-5,5′-(4-chlorobenzylidene)bis[pyrimidine-2,4(1H,3H)-dione]

et al. 2022

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Heterocyclic compounds, including pyrimidine derivatives, exhibit a broad variety of biological and pharmacological activities. In this paper, a previously synthesized novel pyrimidine molecule is proposed, and its pharmaceutical properties are investigated. Computational techniques such as the density functional theory, ADMET evaluation, and molecular docking were applied to elucidate the chemical nature, drug likeness and antibacterial function of molecule. The viewpoint of quantum chemical computations revealed that the molecule was relatively stable and has a high electrophilic nature. The contour maps of HOMO-LUMO and molecular electrostatic potential were analyzed to illustrate the charge density distributions that could be associated with the biological activity. Natural bond orbital (NBO) analysis revealed details about the interaction between donor and acceptor within the bond. Drug likeness and ADMET analysis showed that the molecule possesses the agents of safety and the effective combination therapy as pharmaceutical drug. The antimicrobial activity was investigated using molecular docking. The investigated molecule demonstrated a high affinity for binding within the active sites of antibacterial and antimalarial proteins. The high affinity of the antibacterial protein was proved by its low binding energy (−7.97 kcal/mol) and a low inhibition constant value (1.43 µM). The formation of four conventional hydrogen bonds in ligand–protein interactions confirmed the high stability of the resulting complexes. When compared to known standard drugs, the studied molecule displayed a remarkable antimalarial activity, as indicated by higher binding affinity (B.E. −5.86 kcal/mol & Ki = 50.23 M). The pre-selected molecule could be presented as a promising drug candidate for the development of novel antimicrobial agents.

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Development of a biomarker to monitor target engagement after treatment with dihydroorotate dehydrogenase inhibitors

Pontikos

Leija

Zhao

et al. 2022

Biochemical Pharmacology

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Driving antimalarial design through understanding of target mechanism

Cited by 13 publications

References 99 publications

Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective

Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective

DFT, ADMET and Molecular Docking Investigations for the Antimicrobial Activity of 6,6′-Diamino-1,1′,3,3′-tetramethyl-5,5′-(4-chlorobenzylidene)bis[pyrimidine-2,4(1H,3H)-dione]

Development of a biomarker to monitor target engagement after treatment with dihydroorotate dehydrogenase inhibitors

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