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A computational assessment of alkaloids targeting the plant homeodomain in pygopus2: inhibitory potential and drug-like properties
Abstract
Pygopus2 (Pygo2) is a component of the Wnt signaling pathway, crucial for β-catenin-mediated transcription during normal development. Overexpression of Pygo2 has been linked to various human cancers, including lung, colon, and brain cancers. The plant homeodomain (PHD) finger in Pygo2 intercalates with the methylated histone 3 (H3K4me) tail and the HD1 domain of BCL9, which binds to β-catenin. This interaction highlights the PHD finger as a promising target for designing anti-cancer drugs. Despite the importance of this protein in numerous cancers, no approved drug currently targets it. In this study, we used in silico techniques to identify alkaloids with favourable PHD binding affinities compared to standard compounds. Three alkaloids—discorhabdin W (9.7 Kcal/mol), topsentin A (9.1 Kcal/mol), and dragmacidin A (9.0 Kcal/mol)—emerged as the best candidates, exhibiting stronger binding effects compared to JBC117 (9.2 Kcal/mol), a compound that has been shown to inhibit cancer cell proliferation both ex vivo and in vivo. They also exhibited compliance with Lipinski’s rule, promising drug-like properties, and relatively low toxicity. Molecular dynamics simulations of the three high-affinity protein-ligand complexes revealed considerable conformational flexibility, hinge regions, and low eigenvalues, indicating stable and flexible molecular motions. Based on the findings from this study, these three alkaloids have the potential to be developed as anticancer lead compounds targeting the PHD finger of Pygo2.
Received: 10 July 2024
Accepted: 20 August 2024
Published: 18 September 2024
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DOI: https://dx.doi.org/10.21622/AMPDR.2024.04.2.923
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Copyright (c) 2024 Zechariah Oresanya, Olaide Odesanya, Ibrahim Olaniyi, Christian Agbojo, God's Will Eleanya, Rahmon Kanmodi
Advances in Medical, Pharmaceutical and Dental Research
E-ISSN: 2812-4898
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