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Emergence of a Promising Lead Compound in the Treatment of Triple Negative Breast Cancer: An Insight into Conformational Features and Ligand Binding Landscape of c-Src Protein with UM-164

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Abstract

UM-164, a potent Src/p38 inhibitor, is a promising lead compound for developing the first targeted therapeutic strategy against triple-negative breast cancer (TNBC). However, lack of understanding of conformational features of UM-164 in complex with Src serves a challenge in the rational design of novel Src dual inhibitors. Herein, we provide an in-depth insight into conformational features of Src-UM-164 using different computational approaches. This involved molecular dynamics (MD) simulation, principal component analysis (PCA), thermodynamics calculations, dynamic cross-correlation (DCCM) analysis, and hydrogen bond formation. Findings from this study revealed that (1) the binding of UM-164 to Src induces a more stable and compact conformation; (2) the binding of UM-164 results in increased correlation among the active site residue; (3) the presence of multiple phenyl rings and fluorinated phenyl group in UM-164 contributes to the steric effect; (4) a relatively high-binding free energy estimated for the Src-UM-164 system is affirmative of its experimental potency; (5) hydrophobic packing contributes significantly to the drug binding in Src-UM-164; and (6) observed increase in H-bond distance of interacting residue atoms and Dasatinib compared to UM-164. Findings from this study can serve as a baseline in the design of novel Src inhibitors with dual inhibitory properties.

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Acknowledgements

The authors acknowledge the School of Health Science, University of KwaZulu-Natal, Westville Campus for financial assistance and the Centre for High Performance Computing (CHPC, www.chpc.ac.za) Cape Town, South Africa for computational resources.

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Authors and Affiliations

  1. Molecular Modelling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4000, South Africa

    Umar Ndagi & Mahmoud E. Soliman

  2. School of Laboratory Medicine and Medical Sciences, Discipline of Medical Biochemistry, University of KwaZulu-Natal, Durban, 4000, South Africa

    Ndumiso N. Mhlongo

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  1. Umar Ndagi
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  2. Ndumiso N. Mhlongo
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  3. Mahmoud E. Soliman
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Correspondence to Mahmoud E. Soliman.

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Ndagi, U., Mhlongo, N.N. & Soliman, M.E. Emergence of a Promising Lead Compound in the Treatment of Triple Negative Breast Cancer: An Insight into Conformational Features and Ligand Binding Landscape of c-Src Protein with UM-164. Appl Biochem Biotechnol 185, 655–675 (2018). https://doi.org/10.1007/s12010-017-2677-z

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  • DOI: https://doi.org/10.1007/s12010-017-2677-z

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