Structure-based virtual screening, molecular simulation and free energy calculations of traditional Chinese medicine, ZINC database revealed potent inhibitors of estrogen-receptor α (ERα)

Breast Cancer, a heterogeneous disease at the molecular level, is the most common cause of woman mortality worldwide. We used molecular screening and simulation approaches to target nuclear receptor protein-estrogen receptor alpha (Er alpha) protein to design and develop of specific and compelling drugs from traditional Chinese medicine (TCM), and ZINC database against pathophysiology of breast cancer. Using virtual screening, only six hits TCM22717, TCM23524, TCM31953, while ZINC05632920, ZINC05773243, and ZINC12780336 demonstrated better pharmacological potential than the 4-hydroxytamoxifen (OHT) taken as control. Binding mode of each of the top hit revealed that these compounds could block the main active site residues and block the function of Er alpha protein. Moreover, molecular simulation revealed that the identified compounds exhibit stable dynamics and may induce stronger therapeutic effects in experimental setup. All the complexes reported tighter structural packing and less flexible behaviour. We found that the average hydrogen bonds in the identified complexes remained higher than the control drug. Finally, the total binding free energy demonstrated the best hits among the all. The BF energy results revealed -30.4525 +/- 3.3565 for the 4-hydroxytamoxifen (OHT)/Er alpha complex, for the TCM22717/Er alpha -57.0597 +/- 3.4852 kcal/mol, for the TCM23524/Er alpha complex the BF energy was -56.9084 +/- 3.3737 kcal/mol, for the TCM31953/Er alpha the BF energy was -32.4191 +/- 3.8864 kcal/mol while for the ZINC05632920/Er alpha complex -46.3182 +/- 2.7380, ZINC05773243/Er alpha complex -38.3690 +/- 2.8240, and ZINC12780336/Er alpha complex the BF energy was calculated to be -35.8048 +/- 4.1571 kcal/mol.