Molecular docking and dynamics approach to in silico drug repurposing for inflammatory bowels disease by targeting TNF alpha

Abstract

Inflammatory bowel disease is a chronic disorder of the large intestine with the prevalence of approximately 400 cases in 100000, and it is rising day by day. However, several drugs like sulfasalazine (composed of sulfapyridine and 5-aminosalicylic acid or 5-ASA), corticosteroids, and immunosuppressants manage the disease. But there are no absolute treatments for the pain and inflammation of the disease. TNFα is an important target, and drugs like infliximab and adalimumab have pharmacological potency but with pronounced toxicity. So, we choose this major target TNFα for the virtual screening of US-FDA-approved drugs for its repurposing using the in silico method. The protein TNFα (PDB ID: 2AZ5) with small molecule inhibitor and the US-FDA-approved drug molecules (from Zinc database) were first imported and prepared using Protein Preparation Wizard and LigPrep, respectively, followed by molecular docking, ADMET analysis and prime MMGBSA. After that, the drugs were shortlisted according to dock score, ADMET parameters and MM GBSA dG binding score. After that, the shortlisted drug molecules were subjected to an induced-fit docking analysis. Two of the most promising molecules, ZINC000003830957 (Iopromide) and ZINC000003830635 (Deferoxamine), were chosen for molecular dynamics simulation. Finally, the bioisosteric replacement was used to improve the ADMET properties of these molecules. This research provides an idea for drug exploration and computational tools for drug discovery in treating inflammatory bowel disease.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

Keywords:

• Molecular docking
• molecular dynamics
• ADMET
• TNFα
• Inflammatory bowels disease
• Drug repurposing
• MMGBSA
• Bioisosteric replacement

Acknowledgment

Author Subham Das is thankful to Manipal Academy of Higher Education, Manipal, for Dr. T. M. A. Pai Doctoral Fellowship. The authors are thankful to Manipal-Schrödinger Centre for Molecular Simulations. Manipal College of Pharmaceutical Sciences and Manipal Academy of Higher Education for providing support and facilities for research. Authors acknowledge to ChemDraw and BioRender.com.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author statement

Debojyoti Halder: Conceptualization, in silico modeling, analysis and interpretation of data, original draft preparation. Subham Das: In silico modeling, interpretation of data, data curation and editing. Alex Joseph: Interpretation of data. Jeyaprakash R S: Interpretation of data, supervision.