Explicit water-ligand docking, drug-likeness and molecular dynamics simulation analysis to predict the potency of Boerhavia diffusa plant extract against mutant wilms tumor-1 protein responsible for type 4 nephrotic syndrome.

Abstract

Thestructure and function of a protein are closely connected. Changes in a protein structure can impact on its function. Nephrotic syndrome type 4 (NPHS4) is an uncommon genetic condition caused by mutations in the WT1 gene, which codes for the wilms tumor-1 protein. Several studies have discovered that patients with nephrotic syndromes are resistant to steroid therapy and are likely to develop end-stage renal failure. The use of phytochemicals-based therapeutics is in demand due to their high potential and low toxicity. Based on this context, we employed the Autodock raccoon to screen 67 distinct potent phytochemicals from the Boerhavia diffusa (B.diffusa) plant against the wild type and mutant model at position C388R (cysteine is replaced with arginine at position 388) of the C-terminal DNA binding domain of the wilms tumor-1 protein. Out of 67 active compounds, only 10 compounds (lunamarine, kaempferol, boeravinone B, boeravinone E, boeravinone A, boeravinone F, boeravinone J, boeravinone P, boerhaavic acid and 4',7-dihydroxy-3'-methylflavone) were screened based on drug-likeness properties and binding energy for explicit water ligand docking against wild and mutant model of C-terminal DNA binding domain of wilms tumor-1 protein. Consequently, the hydrated form of boeravinone F and boeravinone A demonstrated the highest binding energy against the protein mutant model described above, the binding energies were -9.56 and -8.96 Kcal/mol, respectively. Followed by explicit water ligand docking the microscopic properties of wild type, mutant, mutant-boeravinone F complex, and mutant-boeravinone A complex systems were evaluated using molecular dynamics simulation steps with 100 ns of trajectory. The findings indicate that, due to mutation the mutant model system had decreasing stability and decreasing compactness nature. However, boeravinone A effectively monitored the mutant system's stability and improved compactness nature after binding with the mutant model. Boeravinone A with the mutant model complex system was determined to have the lowest energy point as compared to other studied systems. The study revealed minimal structural alterations and reduced conformational mobility.