Design of Novel Selective Estrogen Receptor Inhibitors using Molecular Docking and Protein-Ligand Interaction Fingerprint Studies

Aims: The genomic and non-genomic actions of human estrogen receptor α (hERα) play a crucial role in breast epithelial cell proliferation and survival, as well as mammary tumorigenesis. hERα has been proved as a potential target for breast cancer therapy over the last 3 decades. Hence designing novel inhibitors targeting hERα can be a valuable approach in breast cancer therapy. Study Design:  In the present study, the goal is to identify novel hERα inhibitors through molecular docking, AI based virtual screening and interaction fingerprint analysis. Place and Duration of Study: Department of Bioinformatics, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India in between July 2021-sep 2021. Methodology: Molecular docking studies were performed using the human estrogen receptor alpha ligand-binding domain in complex with 4-hydroxytamoxifen (PDB: 3ERT) against existing compounds from literature. The best docked existing compound and co-crystal ligand were subjected to shape screening against 28 million compounds and resulted compounds constituted the hERα inhibitor dataset which was subjected to rigid receptor docking. Further, interaction fingerprint analysis was applied as complimentary method to docking for comparing the similarity of predicted binding poses of proposed leads with that of reference binding pose. Results: Co-crystal ligand (4-OHT) and E99 exhibited better binding affinity among existing ligand set. Rigid receptor docking studies resulted in four lead compounds possessing better docking scores than 4-OHT and E99. Moreover, leads showed favorable absorption, distribution, metabolism, excretion and toxicity properties within the range of 95% FDA approved drugs. Proposed leads showed interactions with binding site residues of hERα similar to that of 4-OHT with better binding affinity. The ability of obtained leads to retrieve actives was validated using receiver operative characteristic (ROC) curve. Conclusion: From above results, it has been observed that the proposed leads have potential to act as novel hERα inhibitors.