Pyridopyrazine derivatives as highly selective histamine H4 receptor antagonist for the treatment of atopic dermatitis: QSAR modeling and molecular docking studies

Mohamed El Yaqoubi; Mouad Lahyaoui; Yousra Seqqat; Taoufiq Saffaj; Bouchaib Ihssane; Nabil Saffaj; Rachid Mamouni; Fouad Ouazzani Chahdi; Fahad M Alshabrmi; Alaa Abdulaziz Alnahari; Saad M. Howladar; Ammar AL-Farga; Youssef Kandri Rodi; Mohamed El Yaqoubi; Mouad Lahyaoui; Yousra Seqqat; Taoufiq Saffaj; Bouchaib Ihssane; Nabil Saffaj; Rachid Mamouni; Fouad Ouazzani Chahdi; Fahad M Alshabrmi; Alaa Abdulaziz Alnahari; Saad M. Howladar; Ammar AL-Farga; Youssef Kandri Rodi

doi:10.3934/Allergy.2024019

AIMS Allergy and Immunology

2024, Volume 8, Issue 4: 303-323. doi: 10.3934/Allergy.2024019

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Research article

Pyridopyrazine derivatives as highly selective histamine H4 receptor antagonist for the treatment of atopic dermatitis: QSAR modeling and molecular docking studies

1.
Laboratory of Applied Organic Chemistry, Faculty of Science and Technology, Sidi Mohamed Ben Abdellah University, USMBA, Po. Box 2626 Fez, Morocco
2.
Laboratory of Biotechnology, Materials and Environment, IbnZohr University, BP 8106-BP 32/S, Riad Salam, CP 80000 Agadir, Morocco
3.
University of Jeddah, College of Science, Department of Biological science, Jeddah, Saudi Arabia
4.
Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia

Received: 16 July 2024 Revised: 04 November 2024 Accepted: 13 November 2024 Published: 09 December 2024

Atopic dermatitis (AD) is a prevalent inflammatory skin condition, primarily characterized by intense pruritus and chronic inflammation. Current therapeutic options targeting the histamine H4 receptor (H4R) have shown limited efficacy in addressing both pruritus and inflammation comprehensively. This study investigates pyridopyrazine derivatives as potential H4R antagonists with a focus on their suitability for AD treatment. To evaluate these compounds, we applied quantitative structure–activity relationship (QSAR) models and molecular docking techniques. A set of 33 pyridopyrazine derivatives was analyzed using principal component regression (PCR), multiple linear regression (MLR), and partial least squares (PLS) methodologies. Molecular descriptors were computed, and collinearity among descriptors was assessed through principal component analysis (PCA). Model performance was evaluated using the root mean square error (RMSE) and coefficient of determination (R²) values, providing insight into predictive accuracy. The PCR model emerged with strong predictive capabilities, showing an RMSE of 1.017 and an R² of 0.897. Furthermore, molecular docking results indicated potent binding interactions with H4R, primarily through hydrophobic and hydrogen-bonding interactions. Notably, compound C11 demonstrated the highest binding affinity, underscoring its potential as a valuable candidate for anti-inflammatory development. In conclusion, pyridopyrazine derivatives, particularly compound C11, exhibit promising anti-inflammatory properties with specific binding efficacy to H4R, suggesting potential for advancing AD treatment options.
- atopic dermatitis,
- histamine H4 receptor,
- QSAR,
- pyridopyrazine derivatives,
- anaphylactic shock,
- hypersensitivity,
- molecular docking
Citation: Mohamed El Yaqoubi, Mouad Lahyaoui, Yousra Seqqat, Taoufiq Saffaj, Bouchaib Ihssane, Nabil Saffaj, Rachid Mamouni, Fouad Ouazzani Chahdi, Fahad M Alshabrmi, Alaa Abdulaziz Alnahari, Saad M. Howladar, Ammar AL-Farga, Youssef Kandri Rodi. Pyridopyrazine derivatives as highly selective histamine H4 receptor antagonist for the treatment of atopic dermatitis: QSAR modeling and molecular docking studies[J]. AIMS Allergy and Immunology, 2024, 8(4): 303-323. doi: 10.3934/Allergy.2024019

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Abstract

Atopic dermatitis (AD) is a prevalent inflammatory skin condition, primarily characterized by intense pruritus and chronic inflammation. Current therapeutic options targeting the histamine H4 receptor (H4R) have shown limited efficacy in addressing both pruritus and inflammation comprehensively. This study investigates pyridopyrazine derivatives as potential H4R antagonists with a focus on their suitability for AD treatment. To evaluate these compounds, we applied quantitative structure–activity relationship (QSAR) models and molecular docking techniques. A set of 33 pyridopyrazine derivatives was analyzed using principal component regression (PCR), multiple linear regression (MLR), and partial least squares (PLS) methodologies. Molecular descriptors were computed, and collinearity among descriptors was assessed through principal component analysis (PCA). Model performance was evaluated using the root mean square error (RMSE) and coefficient of determination (R²) values, providing insight into predictive accuracy. The PCR model emerged with strong predictive capabilities, showing an RMSE of 1.017 and an R² of 0.897. Furthermore, molecular docking results indicated potent binding interactions with H4R, primarily through hydrophobic and hydrogen-bonding interactions. Notably, compound C11 demonstrated the highest binding affinity, underscoring its potential as a valuable candidate for anti-inflammatory development. In conclusion, pyridopyrazine derivatives, particularly compound C11, exhibit promising anti-inflammatory properties with specific binding efficacy to H4R, suggesting potential for advancing AD treatment options.

Abbreviations

atopic dermatitis

ASA+

accessible surface area (positive charge)

ASA−

accessible surface area (negative charge)

ASA_P

accessible surface area (polar)

ast_violation

atom site violation descriptor

H4R

histamine H4 receptor

IC50

inhibitory concentration 50%

IgE

immunoglobulin E

MLR

multiple linear regression

pIC50

negative logarithm of IC50

PCA

principal component analysis

PCR

principal component regression

PLS

partial least squares

QSAR

quantitative structure–activity relationship

R²

coefficient of determination

RMSE

root mean square error

rsynth

resonance synthetic descriptor

T-helper (e.g., TH1, TH17, TH22 cytokines)

VAdjEq

Vertex Adjacency Equality Index

vsurf

molecular surface properties descriptor

vsurf_CP

VSURF coefficient of polarizability

vsurf_CW4

VSURF hydrophobic constant (Cavity 4)

vsurf_HL1

VSURF Hydrophilic–Lipophilic Index 1

vsurf_HL2

VSURF Hydrophilic–Lipophilic Index 2

weinerPol

Wiener Polarity Index (descriptor of molecular branching)

XLSTAT

software for statistical analysis

Zagreb

Zagreb Index Descriptor (topological descriptor)

Conflict of interest

Ammar AL-Farga is an editorial board member for AIMS Allergy and Immunology and was not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests.

Author contributions

M. El Yaqoubi: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Wrote the paper. Y. Seqqat, M. Lahyaoui: Performed the experiments; Wrote the paper. T. Saffaj, I. Bouchaib, N. Saffaj, R. Mamouni, F. Ouazzani Chahdi, Fahad M Alshabrmi, Alaa Abdulaziz Alnahari, Saad M. Howladar, Ammar AL-Farga: Performed the experiments. Kandri Rodi Youssef: Performed the experiments; Contributed reagents, materials, analysis tools or data.

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