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Identification of Kinase-substrate Pairs Using High Throughput Screening
Published on: August 29, 2015
Computational Structural Comparison of Toxoplasma gondii CDPK1 and Human BUB1 kinases: Implications for Selective
João Pedro Bezerra Carvalho1,2, Deborah Antunes1, Daniel Adesse2,3
1Laboratory for Applied Genomics and Bioinnovations, Oswaldo Cruz Institute (IOC - FIOCRUZ), Rio de Janeiro 21040-900, Brazil.
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 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.
Insights
New research identifies potential drug targets for toxoplasmosis by analyzing the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1). Despite sharing a key feature with a human kinase, TgCDPK1 shows promise for selective inhibitor development.
Area of Science:
- Parasitology
- Drug Discovery
- Structural Biology
Background:
- Toxoplasmosis affects a third of the global population, necessitating novel treatments due to drug resistance and current therapy limitations.
- Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) is a crucial drug target for treating toxoplasmosis, essential for parasite survival.
Purpose of the Study:
- To identify novel and selective inhibitors for TgCDPK1.
- To investigate the potential for cross-reactivity with human kinases, specifically BUB1, due to shared structural features.
Main Methods:
- Computational structural analyses of TgCDPK1 and human BUB1.
- Molecular dynamics simulations to compare binding pocket dynamics.
- Virtual screening of apicomplexan kinase inhibitors.
Main Results:
- TgCDPK1 shares a glycine gatekeeper residue with human BUB1, initially posing a challenge for selective inhibitor design.
- Distinct electrostatic properties and binding site architectures were identified between TgCDPK1 and BUB1.
- Molecular dynamics simulations revealed more focused interaction networks in TgCDPK1 compared to BUB1.
- Virtual screening indicated stronger binding affinity for TgCDPK1 over BUB1.
Conclusions:
- Despite structural similarities with human BUB1, TgCDPK1 remains a viable and promising target for selective drug development against toxoplasmosis.
- Further development of selective therapeutics targeting TgCDPK1 is supported by these findings.
