Computational Structural Comparison of Toxoplasma gondii CDPK1 and Human BUB1 kinases: Implications for Selective Inhibitor Design.

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 more focused interaction networks compared to BUB1's dispersed patterns. Virtual screening of apicomplexan kinase inhibitors confirms stronger binding affinity for TgCDPK1 over BUB1, supporting the continued development of selective therapeutics against toxoplasmosis.