Identification of CXCR4 inhibitors as a key therapeutic small molecule in renal fibrosis
Senthil Kumar G1, Kishore N1, Elakkiya Elumalai2
1School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur, Tamil Nadu, India.
Abstract:
The final stage of almost all chronic kidney diseases is renal fibrosis. Simple wounds or persistent inflammation can cause tissue inflammation, which, in the case of the kidney, results in scarring. Vascular sclerosis, tubulointerstitial fibrosis and glomerular fibrosis are all types of kidney fibrosis. Renal damage and fibrosis are caused by elevated expression of CXCR4. This study aimed to identify possible pharmacological agents which could bind to and inhibit isoform I of CXCR4 and determine their strength of interactions. The I-TASSER, Galaxyweb and Robetta were used to predict and refine the structure of the CXCR4 protein. ModBase was used to improve the loops, and then the quality was evaluated by using the ERRAT value (92.15) and Ramachandran plot. The improved 3D structure was subjected to small molecule database docking using Maestro (from Schrodinger) and the glide module. GROMACS was used to simulate molecules with the three top low glide scores and the best ADME properties. The best glide score was achieved by ligand ID 4990 (-11.5). Simulations, free energy landscape and residue decomposition analysis revealed that 4990 interacted more consistently with CXCR4 than the other two small molecules.Communicated by Ramaswamy H. Sarma.
Insights
Researchers identified a potential drug compound, ligand ID 4990, that effectively inhibits CXCR4, a key factor in kidney fibrosis and chronic kidney disease progression. This discovery offers a promising avenue for developing new treatments for renal fibrosis.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Renal fibrosis, the scarring of kidney tissue, is the final stage of most chronic kidney diseases.
- Elevated expression of CXCR4 is a known driver of kidney damage and fibrosis.
Purpose of the Study:
- To identify pharmacological agents that can bind to and inhibit isoform I of CXCR4.
- To determine the interaction strength of potential inhibitory compounds.
Main Methods:
- Protein structure prediction and refinement using I-TASSER, Galaxyweb, Robetta, and ModBase.
- Molecular docking simulations using Maestro and the glide module.
- Molecular dynamics simulations and free energy analysis using GROMACS.
Main Results:
- Ligand ID 4990 demonstrated the strongest binding affinity to CXCR4 with a glide score of -11.5.
- Molecular simulations confirmed consistent interaction of ligand 4990 with CXCR4.
- Ligand 4990 exhibited favorable ADME properties.
Conclusions:
- Ligand ID 4990 is a promising candidate for inhibiting CXCR4.
- This compound could be a potential therapeutic agent for treating renal fibrosis and chronic kidney diseases.
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