Molecular and Protein Interaction Studies for Inhibiting Growth of Human Leukemic Cells: An In Silico Structural Approach to Instigate Drug Discovery

Abstract

Leukemia inhibitory factor (LIF) stimulates the terminal differentiation of the cells of myelogenous leukemia by interacting with gp130 (dimeric) and LIF receptor (LIFR). Janus protein-tyrosine kinases (JAK) and STAT3 get triggered by phosphorylation. This leads to target gene expression and thus inhibition of the growth of leukemic cells occurs. Wet-laboratory experimental studies were involved so far, but the residue-based molecular-level indulgement and structural changes in the protein complexes were not explored hitherto. This study therefore involves X-ray crystal structures of the three proteins. Through molecular docking techniques, the best cluster-sized complex was selected and optimized. Electrostatic surface potential for gp130 protein, net solvent accessibility and an ascent in the ΔG value from −2101.57 kcal/mol to −2124.28 kcal/mol showed spontaneous and firmer interaction after optimization. Conformational fluctuations in gp130 had a shift for increased β-sheet conformation to stabilize the complex. All evaluations were statistically significant. Protein interaction residues and binding patterns revealed that ionic interactions were the predominant ones with Asp and Arg playing chief role. After optimization, even ionic interactions increased to 11. Other interactions including hydrogen bonding ones were also seen. Thus, it might instigate the clinical and pharmaceutical research for drug discovery and to study the mutational impacts upon interaction.