In silico designing of MAD2L2-Rev1 complex inhibitor leads to enhances cell death by chemotherapy

DNA-damaging platinum-based chemotherapeutics (cisplatin, carboplatin, oxaliplatin) have been the first line of treatment for cancer for decades. They act by binding or modifying DNA and blocking replication, generating cytotoxicity and apoptosis of rapidly dividing cancer cells. The translesion synthesis (TLS), a DNA damage tolerance pathway under normal conditions, enable cancerous cell to tolerate DNA damage by employing mutagenic replication at DNA lesion sites. Consequently, chemotherapy promotes the formation of treatment-based mutations which can lead to chemotherapy-resistant of secondary malignancies, increasing morbidity in many cancer patients. TLS activity, in vivo, dependents on MAD2L2 homodimerization and binding to Rev1, for recruitment of the proper Y-family polymerase. Hence, inhibion of the TLS can increate chemotherapy efficiency and reduce development of secondary malignancies. The MAD2L2 dimer structure shows a small cavity at the interface of the two monomers. A model of the MAD2L2 dimer bound to REV1 was created by local docking of Rev1 to the dimer. Molecular dynamics simulation of the complex showed that Rev1 binding induce structural changes and widening of the cavity between the two MAD2L2 monomers. High throughput virtual screening virtual docking of small molecules was carried out in the reshaped cavity of the MAD2L2 homodimer. Two small molecules were discovered that directly bind to MAD2L2 and influence its activity. Both molecules disrupt the formation of the MAD2L2-Rev1 complex causing sensitization to cisplatin and increasing DNA damage both in-vitro and in-vivo.