IN SILICO STUDY OF SOME PHARMACOKINETIC AND PHARMACOLOGICAL PROPERTIES OF THREE ANACARDIC ACIDS IN THE CONTEXT OF SKIN DISEASES

Abstract

Introduction

Melanoma is a highly aggressive skin cancer characterized by pronounced tissue invasion and early metastases, driven by extracellular matrix remodeling. Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play a central role in this process and are key contributors to melanoma progression, making them attractive therapeutic targets. Among natural products, anacardic acids derived from cashew pulp and nut (Anacardium occidentale) have shown relevant biological properties, including antioxidant and anti-inflammatory effects, as well as inhibitory activity against several enzymes such as xanthine oxidase, lipoxygenase, and histone acetyltransferase. These properties suggest a potential role in regulating processes associated with the tumor microenvironment and extracellular matrix remodeling, thereby justifying their investigation in the context of melanoma.

Objectives

To evaluate in silico the physicochemical, pharmacokinetic and toxicological properties of three anacardic acids (monoene, diene and triene) and their modulating potential on metalloproteinases MMP-2 (1QIB) and MMP-9 (2OVX).

Material and Methods

Physicochemical (lipophilicity and aqueous solubility), pharmacokinetic (absorption and metabolism), and toxicological (skin sensitivity, hepatotoxicity, mutagenicity, and carcinogenicity) properties were predicted using SwissADME and ADMET Predictor platforms. Molecular docking was performed in DockThor platform using the crystallographic structures of MMP-2 (PDB:1QIB) and MMP-9 (PDB:2OVX) obtained from the Protein Data Bank. The chemical structures of 6-[8′(Z),11′(Z),14′-pentadecatrienyl] salicylic acid (triene anacardic acid), 6-[8′(Z),11′(Z)-pentadecadienyl] salicylic acid (diene anacardic acid), and 6-[8′(Z)-pentadecenyl] salicylic acid (monoene anacardic acid) were obtained from PubChem database. Protein-ligand interactions were evaluated based on binding energy, intermolecular interaction profiles, and engagement of residues within or proximal to the catalytic site.

Results

In silico analyses indicated that the three anacardic acids exhibit high lipophilicity and low aqueous solubility, favoring skin retention and topical use. Predicted skin absorption was observed; however, CYP2C9 inhibition may limit concomitant oral administration with drugs of narrow therapeutic index. Toxicological predictions showed low risk of mutagenicity, carcinogenicity and hepatotoxicity, despite skin sensitization potential, indicating a mainly local risk manageable through dose and formulation strategies. Docking studies revealed binding of anacardic acids, particularly the diene derivative, to catalytically relevant regions of MMP-2 and MMP-9, suggesting potential enzymatic modulation.

Conclusion

The in silico findings suggest that, in addition to favorable skin permeation and low predicted toxicity, diene anacardic acid showed affinity for both MMPs, indicating potential to modulate targets associated to melanoma tumor microenvironment. Further preclinical studies are required to confirm the therapeutic applicability of anacardic acids in melanoma.