Quantitative structure activity relationship studies of androgen receptor binding affinity of endocrine disruptor chemicals with index of ideality of correlation, their molecular docking, molecular dynamics and ADME studies

Endocrine disrupter chemicals (EDCs) are both natural and man-made chemicals that mimic, block or interfere with human hormonal system. In the present manuscript, QSAR modeling was performed for the androgen disruptors that interfere with biosynthesis, metabolism or action of androgens that causes adverse effects on male reproductive system. A set of 96 EDCs that exhibited affinity towards androgen receptors (Log RBA) in rats were employed for carrying out QSAR studies using Hybrid descriptors (combination of HFG and SMILES) through Monte Carlo Optimization. Using index of ideality of correlation (TF2), five splits were formed and predictability of five models resulting from these splits was assessed by various validation parameters. Models resulted from first split was the top most one with R²_validation = 0.7878. Structural attributes responsible for change in endpoint were studied by employing correlation weights of structural attributes. In order to further validate the model, new EDCs were designed using these attributes. <i>In silico</i> molecular modelling studies were performed to assess the detailed interactions with the receptor. The binding energies of all the designed compounds were observed to be better than lead and are in the range of −10.46 to −14.80. Molecular dynamics simulation of 100 ns was performed for <b>ED01</b> and <b>NED05</b>. The results revealed that the protein-ligand complex bearing <b>NED05</b> was more stable than lead <b>ED01</b> exhibiting better interactions with the receptor. Further, in an attempt to assess their metabolism, ADME studies were evaluated using SwissADME. The developed model enables to predict the characteristics of designed compounds in an authentic way. Communicated by Ramaswamy H. Sarma