Identification of CYP 1B1‐specific candidate inhibitors using combination of in silico screening, integrated knowledge‐based filtering, and molecular dynamics simulations

CYP 1 B 1 is a promising drug target for developing novel drugs against hormonal cancers and hypertension. The development of CYP 1 B 1‐specific inhibitors is hindered mainly due to non‐specific action of known CYP inhibitors. The active site of CYP 1B1 is similar to other cytochromes with different substrate preferences rendering a scope to develop specific inhibitors. We have developed a novel in silico approach for design of selective CYP 1 B 1 inhibitors. The approach consists of deriving details of CYP 1 B 1‐specific molecular interactions from prior studies, which is used to perform screening of CYP 1 B 1 with NCI compounds. The conventional compound screening is also complemented with the concept of cutoff distance between heme ( F e) and compounds. The binding free energies and HB percentage occupancy calculations of 94 compounds of cluster 1 have verified the docking results using MD . The docking interactions in the active‐site cavity of 7 clusters are also taken into account for optimal binding. Hence, we used knowledgebase filtering and MD simulations to enable discovery of selective CYP 1 B 1 inhibitors. The final filtered lead candidates consist of compounds sandwiched between phenylalanine π–π stacking and less than 6 Å from heme ( F e) for enzymatic action. The findings in the study can help development of novel CYP 1 B 1 selective inhibitors.