Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach
Tyrosinases belong to the functional copper-containing proteins family, and their structure contains two copper atoms, in the active site, which are coordinated by three histidine residues. The biosynthesis of melanin in melanocytes has two stages depending on the actions of the natural substrates L...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-05-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/26/10/2875 |
| _version_ | 1797534312049934336 |
|---|---|
| author | Richelly Cardoso Renan Valente Clauber Henrique Souza da Costa João Lidio da S. Gonçalves Vianez Kauê Santana da Costa Fábio Alberto de Molfetta Cláudio Nahum Alves |
| author_facet | Richelly Cardoso Renan Valente Clauber Henrique Souza da Costa João Lidio da S. Gonçalves Vianez Kauê Santana da Costa Fábio Alberto de Molfetta Cláudio Nahum Alves |
| author_sort | Richelly Cardoso |
| collection | DOAJ |
| description | Tyrosinases belong to the functional copper-containing proteins family, and their structure contains two copper atoms, in the active site, which are coordinated by three histidine residues. The biosynthesis of melanin in melanocytes has two stages depending on the actions of the natural substrates L-DOPA and L-tyrosine. The dysregulation of tyrosinase is involved in skin cancer initiation. In the present study, using molecular modeling tools, we analyzed the inhibition activity of tyrosinase activity using kojic acid (KA) derivatives designed from aromatic aldehydes and malononitrile. All derivatives showed conformational affinity to the enzyme active site, and a favorable distance to chelate the copper ion, which is essential for enzyme function. Molecular dynamics simulations revealed that the derivatives formed promising complexes, presenting stable conformations with deviations between 0.2 and 0.35 Å. In addition, the investigated KA derivatives showed favorable binding free energies. The most stable KA derivatives showed the following binding free energies: −17.65 kcal mol<sup>−1</sup> (D6), −18.07 kcal mol<sup>−1</sup> (D2), −18.13 (D5) kcal mol<sup>−1</sup>, and −10.31 kcal mol<sup>−1</sup> (D4). Our results suggest that these derivatives could be potent competitive inhibitors of the natural substrates of L-DOPA (−12.84 kcal mol<sup>−1</sup>) and L-tyrosine (−9.04 kcal mol<sup>−1</sup>) in melanogenesis. |
| first_indexed | 2024-03-10T11:28:50Z |
| format | Article |
| id | doaj.art-7fe69659850b4b719dae97624ec8d1c3 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T11:28:50Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-7fe69659850b4b719dae97624ec8d1c32023-11-21T19:27:32ZengMDPI AGMolecules1420-30492021-05-012610287510.3390/molecules26102875Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling ApproachRichelly Cardoso0Renan Valente1Clauber Henrique Souza da Costa2João Lidio da S. Gonçalves Vianez3Kauê Santana da Costa4Fábio Alberto de Molfetta5Cláudio Nahum Alves6Laboratório de Modelagem Molecular, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará–UFPA, Guamá, Belém-PA 66075-10, BrazilLaboratório de Sistemas Moleculares Complexos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará–UFPA, Guamá, Belém-PA 66075-10, BrazilLaboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará–UFPA, Guamá, Belém-PA 66075-10, BrazilCenter of Technological Innovation, Evandro Chagas Institute, Ministry of Health, Ananindeua-PA 67030-000, BrazilLaboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará–UFPA, Guamá, Belém-PA 66075-10, BrazilLaboratório de Modelagem Molecular, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará–UFPA, Guamá, Belém-PA 66075-10, BrazilLaboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará–UFPA, Guamá, Belém-PA 66075-10, BrazilTyrosinases belong to the functional copper-containing proteins family, and their structure contains two copper atoms, in the active site, which are coordinated by three histidine residues. The biosynthesis of melanin in melanocytes has two stages depending on the actions of the natural substrates L-DOPA and L-tyrosine. The dysregulation of tyrosinase is involved in skin cancer initiation. In the present study, using molecular modeling tools, we analyzed the inhibition activity of tyrosinase activity using kojic acid (KA) derivatives designed from aromatic aldehydes and malononitrile. All derivatives showed conformational affinity to the enzyme active site, and a favorable distance to chelate the copper ion, which is essential for enzyme function. Molecular dynamics simulations revealed that the derivatives formed promising complexes, presenting stable conformations with deviations between 0.2 and 0.35 Å. In addition, the investigated KA derivatives showed favorable binding free energies. The most stable KA derivatives showed the following binding free energies: −17.65 kcal mol<sup>−1</sup> (D6), −18.07 kcal mol<sup>−1</sup> (D2), −18.13 (D5) kcal mol<sup>−1</sup>, and −10.31 kcal mol<sup>−1</sup> (D4). Our results suggest that these derivatives could be potent competitive inhibitors of the natural substrates of L-DOPA (−12.84 kcal mol<sup>−1</sup>) and L-tyrosine (−9.04 kcal mol<sup>−1</sup>) in melanogenesis.https://www.mdpi.com/1420-3049/26/10/2875skin cancermelanogenesistyrosinasekojic acid derivativesmolecular dockingmolecular dynamics |
| spellingShingle | Richelly Cardoso Renan Valente Clauber Henrique Souza da Costa João Lidio da S. Gonçalves Vianez Kauê Santana da Costa Fábio Alberto de Molfetta Cláudio Nahum Alves Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach Molecules skin cancer melanogenesis tyrosinase kojic acid derivatives molecular docking molecular dynamics |
| title | Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach |
| title_full | Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach |
| title_fullStr | Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach |
| title_full_unstemmed | Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach |
| title_short | Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach |
| title_sort | analysis of kojic acid derivatives as competitive inhibitors of tyrosinase a molecular modeling approach |
| topic | skin cancer melanogenesis tyrosinase kojic acid derivatives molecular docking molecular dynamics |
| url | https://www.mdpi.com/1420-3049/26/10/2875 |
| work_keys_str_mv | AT richellycardoso analysisofkojicacidderivativesascompetitiveinhibitorsoftyrosinaseamolecularmodelingapproach AT renanvalente analysisofkojicacidderivativesascompetitiveinhibitorsoftyrosinaseamolecularmodelingapproach AT clauberhenriquesouzadacosta analysisofkojicacidderivativesascompetitiveinhibitorsoftyrosinaseamolecularmodelingapproach AT joaolidiodasgoncalvesvianez analysisofkojicacidderivativesascompetitiveinhibitorsoftyrosinaseamolecularmodelingapproach AT kauesantanadacosta analysisofkojicacidderivativesascompetitiveinhibitorsoftyrosinaseamolecularmodelingapproach AT fabioalbertodemolfetta analysisofkojicacidderivativesascompetitiveinhibitorsoftyrosinaseamolecularmodelingapproach AT claudionahumalves analysisofkojicacidderivativesascompetitiveinhibitorsoftyrosinaseamolecularmodelingapproach |