Computational Structural Comparison of Toxoplasma gondii CDPK1 and Human BUB1 kinases: Implications for Selective Inhibitor Design
João Pedro Bezerra Carvalho, Deborah Antunes, Daniel Adesse, Ana Carolina Guimarães
TL;DR
Researchers compared two kinases from a parasite and humans to design drugs that target the parasite without affecting human cells.
Contribution
The study reveals structural similarities and differences between TgCDPK1 and BUB1 kinases, enabling selective inhibitor design.
Findings
TgCDPK1 and BUB1 share a glycine gatekeeper but differ in electrostatic and structural properties.
Molecular dynamics show TgCDPK1 has more focused interaction networks than BUB1.
Virtual screening confirms stronger inhibitor binding to TgCDPK1 over BUB1.
Abstract
Toxoplasmosis, affecting one-third of the global human population, urgently requires new therapeutic strategies due to current treatment limitations and drug resistance. Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) is a promising drug target due to its essential role in parasite survival and its presumed unique glycine gatekeeper residue. Aiming at identifying new and selective inhibitors of TgCDPK1, we performed computational structural analyses and unexpectedly found that a human kinase (BUB1), despite having only 14% sequence identity, shares this glycine gatekeeper with TgCDPK1, which initially raised concerns for selective inhibitor development. Subsequent analyses revealed distinct electrostatic properties and binding site architectures between these kinases. Molecular dynamics simulations demonstrate differential binding pocket dynamics, with TgCDPK1 showing…
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Taxonomy
TopicsToxoplasma gondii Research Studies · Ubiquitin and proteasome pathways · Autophagy in Disease and Therapy