Multi-step in silico study of potential estrogen receptor alpha modulators: Integrating hierarchical virtual screening, pharmacokinetics, MM-GBSA, molecular dynamics, and DFT studies

Estrogen receptor alpha (ERα) plays a crucial role in the progression and proliferation of BC cells. Although anti-estrogen treatments such as tamoxifen have significantly improved treatment outcomes, but their prolonged use is associated with therapeutic resistance and adverse effects. These limitations emphasize the urgent necessity for novel, safer ERα targeting molecules. This research investigates pyrimidine derivatives as potential ERα modulators, employing an advanced multi-step computational approach including high-throughput structure-based virtual screening, docking analysis, molecular dynamics simulation, and density functional theory calculation to screen promising inhibitors targeting the ERα ligand-binding domain involved in tumor angiogenesis. A pyrimidine-based dataset containing 2,10,798 molecules was subsequently obtained from PubChem and subjected to structure-based virtual screening, and docked in XP and SP mode, on binding cavity of ERα protein PDB ID 4XI3. Twenty molecules showing favourable docking interactions were shortlisted for further pharmacokinetic profiling and MM-GBSA binding free energy estimation. The multistep screening identified HIT 1 compound with a superior docking score (-13.901 kcal/mol) as compared to standard drug raloxifene (-12.136 kcal/mol), as well as favourable pharmacokinetic properties and enhanced MM-GBSA binding free energies. To examine the dynamic stability of complex, a 500ns molecular dynamic simulation was performed for the ERα-HIT 1 system. In addition, DFT calculations supported its electronic stability and bio-feasibility through analysing its HOMO-LUMO energy gap. These results suggest that the HIT 1 molecule serves as a promising scaffold for the development of a novel ERα modulator with potential to suppress ERα-mediated BC progression and angiogenesis.