Identification of novel Plasmodium falciparum dihydroorotate dehydrogenase inhibitors for malaria using in silico studies

Alzain, Abdulrahim A.; Ahmed, Zain Alsharf M.; Mahadi, Mariam A.; Khairy, Elaf A.; Albadwi, Fatima A.

doi:10.1016/j.sciaf.2022.e01214

Cited by 9 publications

(15 citation statements)

References 66 publications

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“…Arg265 contributes to the contact surface of the Pf DHODH binding pocket, as does His185, forming hydrogen bonds: Arg265 and His185, which form hydrogen bonding interactions with the triazolopyrimidine and amino groups of the ligands. Alzain et al also noted the relevance of Arg265 for ligand binding at the active site of the enzyme. The R265A mutation revealed a decrease in the inhibitory properties of some compounds at the DHODH site …”

Section: Resultsmentioning

confidence: 97%

“…Likewise, Phe171 has also been shown to exhibit halogen interactions with the two [i(C7)F] ligands. Leu187 and Phe171 promoted hydrophobic interactions, as well as Ile179, Cys184, Leu191, Leu197, and Tyr168 in a computational screening study of Pf DHODH inhibitors . Phe171 has the ability to promote several conformations, allowing the enzyme to carry substituents of different sizes in the hydrophobic pocket next to this residue.…”

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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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: 97%

Section: Resultsmentioning

confidence: 99%

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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“…The techniques employed in this research has found various applications in other antimalarial derivatives such as in the top 10 hits in Alzain's research [ 2 ] subjected to ADME calculation. Where, all ten of the compounds show favorable ADME characteristics that will aid in future studies and validations.…”

Section: Discussionmentioning

confidence: 99%

“…A never-ending series of studies were reported on the molecular docking and pharmacokinetic properties of antimalarial medications. The works of Qidwai [ 24 ], Alzain et al [ 2 ], Tahghighi [ 30 ] and Shah [ 26 ] are only a few examples. The current study examines the drug-likeness and pharmacokinetic properties of the generated derivatives, as well as docking them against the Plasmodium falciparum dihydroorotate dehydrogenase, Pf- DHODH protein, to predict ligand binding interactions and explain why they occur.…”

Section: Introductionmentioning

confidence: 99%

Virtual screening and molecular dynamic simulations of the antimalarial derivatives of 2-anilino 4-amino substituted quinazolines docked against a Pf-DHODH protein target

Ibrahim

Uzairu

Shallangwa

et al. 2022

Egypt J Med Hum Genet

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Background The processes of drug development and validation are too expensive to be subjected to experimental trial and errors. Hence, the use of the insilico approach becomes imperative. To this effect, the drug-likeness and pharmacokinetic properties of the ten (10) previously designed derivatives of 2-anilino 4-amino substituted quinazolines were carried out. Their predicted ligand binding interactions were also carried out by docking them against the Plasmodium falciparum dihydroorotate dehydrogenase (Pf-DHODH) protein target, and the stability of the complex was determined through dynamic simulations. The drug-likeness and pharmacokinetic characteristics were estimated using the online SwissADME software, while the Molegro Virtual Docker (MVD) software was used for molecular docking. And the dynamic simulation was performed for the duration of 100 ns to verify the stability of the docked complex, with the aid of a Schrödinger program, Desmond. Results The designed derivatives were all found to pass the Lipinski test of drug likeness, while the pharmacokinetic studies result that the skin permeability and molar refractivity values of the derivatives are both within the limits. In addition, except for derivative C-01, most of the derivatives have strong gastrointestinal absorptions and lack Pgp substrate. Furthermore, no derivative inhibited CYP1A2, CYP2C9, or CYP2C19. The docking studies show the better binding affinities between the ligands and Pf-DHODH than those between the atovaquone or chloroquine standards. The derivative C-02, {5-((6,7-dimethoxy-4-((3-nitrobenzyl)amino)quinazolin-2-yl)amino)-2-fluorobenzaldehyde} was found to be the most stable derivative, with a re-rank docking score of − 173.528 kcal/mol and interaction energy of − 225.112 kcal/mol. The dynamic simulation analysis shows that the derivative C-02 forms a stable complex with the protein target over the simulation time. Conclusions The ability of these ligands to form hydrogen bonds, as well as various other interactions, was cited as a factor responsible for their better binding affinity. These findings could aid further the development of enhanced antimalarial drugs.

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“…Three active C5‐mimic diarylpentanoid molecules (compounds 54–56 ) were proposed, which were further investigated using molecular dynamics to obtain a structural understanding of the ligand–protein complex. [ 173 ] Based on these results, compounds 54–56 need to be experimentally validated to confirm their potential as promising antimalarial agents.…”

Section: In Silico Studymentioning

confidence: 99%

Diarylpentanoids, the privileged scaffolds in antimalarial and anti‐infectives drug discovery: A review

Ramli,

Mohd Faudzi

2023

Archiv der Pharmazie

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Asia is a hotspot for infectious diseases, including malaria, dengue fever, tuberculosis, and the pandemic COVID‐19. Emerging infectious diseases have taken a heavy toll on public health and the economy and have been recognized as a major cause of morbidity and mortality, particularly in Southeast Asia. Infectious disease control is a major challenge, but many surveillance systems and control strategies have been developed and implemented. These include vector control, combination therapies, vaccine development, and the development of new anti‐infectives. Numerous newly discovered agents with pharmacological anti‐infective potential are being actively and extensively studied for their bioactivity, toxicity, selectivity, and mode of action, but many molecules lose their efficacy over time due to resistance developments. These facts justify the great importance of the search for new, effective, and safe anti‐infectives. Diarylpentanoids, a curcumin derivative, have been developed as an alternative with better bioavailability and metabolism as a therapeutic agent. In this review, the mechanisms of action and potential targets of antimalarial drugs as well as the classes of antimalarial drugs are presented. The bioactivity of diarylpentanoids as a potential scaffold for a new class of anti‐infectives and their structure–activity relationships are also discussed in detail.

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Identification of novel Plasmodium falciparum dihydroorotate dehydrogenase inhibitors for malaria using in silico studies

Cited by 9 publications

References 66 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

Virtual screening and molecular dynamic simulations of the antimalarial derivatives of 2-anilino 4-amino substituted quinazolines docked against a Pf-DHODH protein target

Diarylpentanoids, the privileged scaffolds in antimalarial and anti‐infectives drug discovery: A review

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