Abstract
Simple Summary The role of persistent organic pollutants (POPs) in breast cancer progression and their bioaccumulation in adipose tissue has been reported. We used a computational approach to study molecular interactions of POPs with breast cancer proteins and identified natural and synthetic compounds to inhibit these interactions. Moreover, for comparative analysis, standard drugs and screened compounds were also docked against estrogen receptor alpha (ER alpha) and identification of the finest inhibitor was performed using in-silico mining and drug-drug interaction (DDI) network approaches. Based on scoring values, short-chained chlorinated paraffins demonstrated strong interactions with ER alpha compared to organo-chlorines and PCBs. Synthetic and natural compounds demonstrating strong associations with the active site of the ER alpha protein could be potential candidates to treat breast cancer specifically caused by POPs and other organic toxins and can be used as an alternative to standard drugs. The strong association between POPs and breast cancer in humans has been suggested in various epidemiological studies. However, the interaction of POPs with the ER alpha protein of breast cancer, and identification of natural and synthetic compounds to inhibit this interaction, is mysterious yet. Consequently, the present study aimed to explore the interaction between POPs and ER alpha using the molecular operating environment (MOE) tool and to identify natural and synthetic compounds to inhibit this association through a cluster-based approach. To validate whether our approach could distinguish between active and inactive compounds, a virtual screen (VS) was performed using actives (627 compounds) as positive control and decoys (20,818 compounds) as a negative dataset obtained from DUD-E. Comparatively, short-chain chlorinated paraffins (SCCPs), hexabromocyclododecane (HBCD), and perfluorooctanesulfonyl fluoride (PFOSF) depicted strong interactions with the ER alpha protein based on the lowest-scoring values of -31.946, -18.916, -17.581 kcal/mol, respectively. Out of 7856 retrieved natural and synthetic compounds, sixty were selected on modularity bases and subsequently docked with ER alpha. Based on the lowest-scoring values, ZINC08441573, ZINC00664754, ZINC00702695, ZINC00627464, and ZINC08440501 (synthetic compounds), and capsaicin, flavopiridol tectorgenin, and ellagic acid (natural compounds) showed incredible interactions with the active sites of ER alpha, even more convening and resilient than standard breast cancer drugs Tamoxifen, Arimidex and Letrozole. Our findings confirm the role of POPs in breast cancer progression and suggest that natural and synthetic compounds with high binding affinity could be more efficient and appropriate candidates to treat breast cancer after validation through in vitro and in vivo studies.