In Silico insight to identify Potential Inhibitors of BUB1B from Mushroom bioactive compounds to Prevent Breast cancer metastasis

Abstract

BUB1B (BUB1 Mitotic Checkpoint Serine/Threonine Kinase B) gene belongs to the spindle assembly checkpoint protein family, proven to be associated with many kinds of cancers. Protein kinases are crucial in metaphase to anaphase cellular transition. It is a primary element of spindle assembly checkpoint (SAC). This SAC is responsible for guarding the proper chromosomal segregation while any chromosomal instability hinders its normal functioning. The chromosomal instability may lead to cancer progression. And it occurs mainly due to overexpression of BUB1B in many cancer types especially in breast cancer metastasis. This could be controlled by designing proper inhibitor of this gene. For this purpose, there are proved existence of various mushroom compounds possessing some important medicinal properties with proven anti-cancerous effects. Proper screening and identification of molecules having these anti-cancerous effects and showing affinity against BUB1B with inhibition properties could be obtained from these compounds. So this study has incorporated 70 bioactive compounds (handpicked through literature mining) of distinct mushrooms that were considered and explored for identifying a suitable drug candidate. Their ADME/T properties were obtained to predict the drug-likeness of these 70 mushroom compounds based on Lipinskis rule of 5 (RO5). The screening of these bioactive compounds and subsequent molecular docking against BUB1B provided compounds with the best conformation-based binding affinity. The best 2 complexes, i.e., BUB1B-Lepiotaprocerin D and BUB1B-Peptidoglycan, were subjected to the molecular dynamics simulation. Both the complexes were observed for their affinity, stability, and flexibility in protein-ligand complex systems. The MD simulation study revealed that Lepiotaprocerin D has an energetically favorable binding affinity with BUB1B. Results showed that the formation of a hydrogen bond between ASN123, SER157 residue and Lepiotaprocerin D has strengthened the affinity of Lepiotaprocerin D with BUB1B. Hence, this study identified Lepiotaprocerin D as a potential and novel inhibitor for BUB1B that could be a plausible drug candidate for checking and controlling the spread of breast cancer metastasis.