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In Silico Mutagenesis in Recombinant Human Keratinocyte Growth Factor: Improvement of Stability and Activity in Addition to Decrement Immunogenicity Publisher Pubmed



Kalhor H1 ; Sadeghi S2 ; Marashiyan M3 ; Enssi M4 ; Kalhor R5 ; Ganji M6 ; Rahimi H3
Authors
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Authors Affiliations
  1. 1. Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
  2. 2. Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
  4. 4. Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, IR, Iran
  5. 5. Department of Genetics, Colleague of Sciences, Kazerun Branch, Islamic Azad University, Kazerun, Iran
  6. 6. Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Source: Journal of Molecular Graphics and Modelling Published:2020


Abstract

The recombinant human keratinocyte growth factor (rhKGF) is clinically applied to decrease the incidence and duration of cancer therapeutic agents. Particularly, it is extensively used for oral mucositis after chemotherapy-induced damage of different human cancers. However, the usage of rhKGF in treatment is limited owing to its short half-life, poor stability, immunogenicity, tendency to aggregate, and side effects. Therefore, there is a need to enhance the stability and to reduce immunogenicity of rhKGF for therapeutic applications. In this study, the stability, activity, and immunogenicity of rhKGF were improved using computational methods. The several mutations were generated based on sequence alignment, amino acids physic-chemical properties, and the structure simulation. The 3D structure of rhKGF and proposed mutants were predicted by Modeller v9.15 program, and then were evaluated using PROSESS, PROCHECK, and ProSA web tools. Afterwards, the effect of these mutants on rhKGF structure, stability, activity, and its interaction with fibroblast growth factor receptor2-IIb (FGFR2-IIb) was analyzed through utilizing GROMACS molecular dynamics simulations and docking tools, respectively. Also, binding free energies were calculated by the Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method. We found that F63Y, R121K, and combine1 (K38R, F63Y, K72E, N105S) mutants lead to reduction of the number of T-cell epitopes. However, all of the selected mutants, except for R121K, could considerably increase stability and affinity of the rhKGF to FGFR2-IIb, in silico. In conclusion, this study, for the first time, offered that the combine1 and F63Y mutants could highly improve the stability and activity of rhKGF and even reduce immunogenicity without having any significant effect on the biological functions of rhKGF. © 2020 Elsevier Inc.
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