Computational analysis of phytochemical inhibitors targeting the CRESS domain of the replicase associated protein of tomato leaf curl New Delhi virus

Plant viruses pose a major threat to global agriculture by reducing crop yield and quality, leading to significant economic losses. Among them, begomoviruses, such as tomato leaf curl New Delhi virus (ToLCNDV), are highly destructive in warm climates and are transmitted by whitefly (Bemisia tabaci). The replication-associated protein (Rep) of ToLCNDV, particularly its N-terminal CRESS (Circular Rep-Encoding Single Stranded) domain, is essential for initiating viral DNA replication and represents a promising target for antiviral intervention. In this study, the ToLCNDV Rep sequence was analyzed to identify the CRESS domain (residues 8–116), and a high-confidence 3D structural model was generated via homology modeling and validated using Ramachandran plot analysis via the PROCHECK tool. A library of 2847 phytochemicals was screened against the CRESS domain using molecular docking, with flavonoids emerging as the predominant class among top-scoring compounds. The highest-affinity ligands—1,2,3,4-Tetragalloyl-α-d-glucose (− 11.50 kcal/mol), Cyanin (− 11.03 kcal/mol), and Delphinidin 3-O-sophoroside (− 11.01 kcal/mol)—formed stable interactions with key conserved residues in the binding pocket, including ASP119, ARG121, GLY125, ASN13, and ALA158. Subsequent MM-GBSA binding energy calculations and molecular dynamics simulations confirmed the stability and thermodynamic favorability of these interactions. Notably, ligand binding at these conserved residues suggests potential inhibition of Rep-mediated DNA replication, a mechanism not previously explored for plant DNA viruses. This study highlights flavonoid-based phytochemicals as promising antiviral candidates targeting the CRESS domain of ToLCNDV and provides a foundation for future experimental validation and development of novel plant viral inhibitors.