Design of integrin inhibitors by using molecular modelling methods

In this study, we aimed to design novel integrin inhibitors by using molecular modelling methods based on disintegrins obtained from snake venom in order to inhibit effects of integrins, which protein group is responsible for cell adhesion and signal transduction on cancer development. For this purpose, the aminoacid sequences of the disintegrin molecules which are containing RGD motif were taken from UniProt database. The ratios of aminoacids that take place in the right and left side of the RGD motif were calculated. According to these calculated ratios, aminoacid combinations were formed by positioning the RGD motif at the beginning, middle and end of the cyclic peptide sequences. In addition to natural aminoacids, 4 non-canonical aminoacids that were formed by modifying R and D aminoacids in RGD motif were added to Rosetta database and non-RGD combinations of aminoacids were formed. Cyclic peptides were generated by using Rosetta 3.9 modelling software. The generated cyclic peptides were aligned at the binding site of αvβ3 integrin, which was selected and prepared as receptor structure, and docking simulations were performed in Rosetta 3.9 software. Molecular dynamics simulations of 7 molecules which gave the best binding score after docking simulations were performed on Gromacs 2018.3 software.