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Identification of 1, 2, 4-Triazine and Its Derivatives Against Lanosterol 14-Demethylase (CYP51) Property of Candida albicans: Influence on the Development of New Antifungal Therapeutic Strategies.

ABSTRACT: This research aims to find out whether the 1, 2, 4-triazine and its derivatives have antifungal effects and can protect humans from infection with Candida albicans. Molecular docking and molecular dynamic simulation are widely used in modern drug design to target a particular protein with a ligand. We are interested in using molecular docking and molecular dynamics modeling to investigate the interaction between the derivatives of 1, 2, 4-triazine with enzyme Lanosterol 14-demethylase (CYP51) of Candida albicans. The inhibition of Candida albicans CYP51 is the main goal of our research. The 1, 2, 4-triazine and its derivatives have been docked to the CYP51 enzyme, which is involved in Candida albicans Multidrug Drug Resistance (MDR). Autodock tools were used to identify the binding affinities of molecules against the target proteins. Compared to conventional fluconazole, the molecular docking results indicated that each drug has a high binding affinity for CYP51 proteins and forms unbound interactions and hydrogen bonds with their active residues and surrounding allosteric residues. The docking contacts were made using a 10 ns MD simulation with nine molecules. RMSD, RMSF, hydrogen bonds, and the Rg all confirm these conclusions. In addition, these compounds were expected to have a favorable pharmacological profile and low toxicity. The compounds are being offered as scaffolds for the development of new antifungal drugs and as candidates for future in vitro testing.

SUBMITTER: Verma AK

PROVIDER: S-EPMC8996309 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Identification of 1, 2, 4-Triazine and Its Derivatives Against Lanosterol 14-Demethylase (CYP51) Property of <i>Candida albicans:</i> Influence on the Development of New Antifungal Therapeutic Strategies.

Verma Abhishek Kumar AK Majid Aarfah A Hossain Md Shahadat MS Ahmed Sk Faisal SF Ashid Mohammad M Bhojiya Ali Asger AA Upadhyay Sudhir K SK Vishvakarma Naveen Kumar NK Alam Mudassir M

Frontiers in medical technology 20220328

This research aims to find out whether the 1, 2, 4-triazine and its derivatives have antifungal effects and can protect humans from infection with <i>Candida albicans</i>. Molecular docking and molecular dynamic simulation are widely used in modern drug design to target a particular protein with a ligand. We are interested in using molecular docking and molecular dynamics modeling to investigate the interaction between the derivatives of 1, 2, 4-triazine with enzyme Lanosterol 14-demethylase (CY ...[more]

PMID: 35419560

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Project description:Azole resistant fungal infections remain a health problem for the immune compromised. Current therapies are limited due to rises in new resistance mechanisms. Therefore, it is important to identify new drug targets for drug discovery and novel therapeutics. Arv1 (are1 are2 required for viability 1) function is highly conserved between multiple pathogenic fungal species. Candida albicans (C. albicans) cells lacking CaArv1 are azole hypersusceptible and lack virulence. Saccharomyces cerevisiae (S. cerevisiae) Scarv1 cells are also azole hypersusceptible, a phenotype reversed by expression of CaArv1, indicating conservation in the molecular mechanism for azole susceptibility. To define the relationship between Arv1 function and azole susceptibility, we undertook a structure/function analysis of ScArv1. We identified several conserved amino acids within the ScArv1 homology domain (ScAhd) required for maintaining normal azole susceptibility. Erg11 lanosterol 14-α-demethylase is the rate-limiting enzyme in sterol biosynthesis and is the direct target of azole antifungals, so we used our ScArv1 mutants in order to explore the relationship between ScArv1 and ScErg11. Specific ScArv1 mutants ectopically expressed from a low copy plasmid were unable to restore normal azole susceptibility to Scarv1 cells and had reduced Erg11 protein levels. Erg11 protein stability depended on its ability to form a heterodimeric complex with Arv1. Complex formation was required for maintaining normal azole susceptibility. Scarv1 cells expressing orthologous CaArv1 mutants also had reduced CaErg11 levels, were unable to form a CaArv1-CaErg11 complex, and were azole hypersusceptible. Scarv1 cells expressing CaArv1 mutants unable to interact with CaErg11 could not sustain proper levels of the azole resistant CaErg11Y132F F145L protein. Caarv1/Caarv1 cells expressing CaArv1 mutants unable to interact with CaErg11 were found to lack virulence using a disseminated candidiasis mouse model. Expressing CaErg11Y132F F145L did not reverse the lack of virulence. We hypothesize that the role of Arv1 in Erg11-dependent azole resistance is to stabilize Erg11 protein level. Arv1 inhibition may represent an avenue for treating azole resistance.

Dataset Information

Identification of 1, 2, 4-Triazine and Its Derivatives Against Lanosterol 14-Demethylase (CYP51) Property of Candida albicans: Influence on the Development of New Antifungal Therapeutic Strategies.

Publications

Identification of 1, 2, 4-Triazine and Its Derivatives Against Lanosterol 14-Demethylase (CYP51) Property of <i>Candida albicans:</i> Influence on the Development of New Antifungal Therapeutic Strategies.

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