Identification of novel inhibitors of tetranectin–plasminogen interaction to suppress breast cancer invasion: an integrated computational and cell-based investigation

Abstract

Tetranectin–plasminogen interaction plays a defining role in extracellular matrix degradation, enabling tumor cell invasion and metastasis. This interaction occurs via the carbohydrate recognition domain (CRD) and Kringle 4 domain of tetranectin and plasminogen, respectively, leading to activation of the plasminogen-cascade that triggers the proteolytic processes. Thus targeting this interaction represents an important strategy to suppress tumor cell migration and invasion. In this direction, we attempted to target the CRD of tetranectin to inhibit its interaction with the Kringle-4 domain of plasminogen using natural bioactive compounds. A cheminformatics pipeline for drug designing and screening was utilized to obtain lead compound(s) that exhibit conformationally and energetically viable CRD binding. Out of 206 compounds screened, diosgenin and scytonemin displayed the most favorable interactions with CRD. Short-term molecular dynamics simulations of 20 ns were employed to further study the conformational stability of both compounds with tetranectin CRD which reflected at the increased stability of diosgenin in the CRD binding pocket compared to scytonemin. Finally, an extended molecular dynamic simulation of 100 ns affirmed the robust and stable interaction of diosgenin with CRD. Furthermore, diosgenin was observed to exert a pronounced anti-proliferative effect on high tetranectin-expressing MDA-MB-231 breast cancer cells. The inhibitory effect of diosgenin on the tetranectin–plasminogen interaction was corroborated by the reduced migration and invasiveness of MDA-MB-231 cells under diosgenin treatment. Overall the study presents an alternate and safer approach to impede breast cancer metastasis and delineates the novel anti-metastatic activity of diosgenin.

Communicated by Ramaswamy H. Sarma

Keywords:

• Tetranectin
• plasminogen
• diosgenin
• migration
• invasion
• extracellular matrix

Disclosure statement

The authors have no conflict of interest to mention.

Data availability statement

All the data will be made available on reasonable request to the corresponding author

Additional information

Funding

Authors would like to thank Indian Council of Medical Research (ICMR), New Delhi, India for financial support (5/10/15/CAR-SMVDV/2018-RBMCH) to the Laboratory.