Applied Biochemistry and Biotechnology

, Volume 185, Issue 3, pp 655–675 | Cite as

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

  • Umar Ndagi
  • Ndumiso N. Mhlongo
  • Mahmoud E. Soliman


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.


Src Molecular dynamics TNBC UM-164 Dual kinase inhibitor and DFG-out 



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, Cape Town, South Africa for computational resources.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there is no conflict of interests.


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© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Umar Ndagi
    • 1
  • Ndumiso N. Mhlongo
    • 2
  • Mahmoud E. Soliman
    • 1
  1. 1.Molecular Modelling and Drug Design Research Group, School of Health SciencesUniversity of KwaZulu-NatalDurbanSouth Africa
  2. 2.School of Laboratory Medicine and Medical Sciences, Discipline of Medical BiochemistryUniversity of KwaZulu-NatalDurbanSouth Africa

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