Three new scorpion chloride channel toxins as potential anti-cancer drugs: Computational prediction of the interactions with hMMP-2 by docking and Steered Molecular Dynamics Simulations

Scorpion venom is a rich source of toxins which have great potential to develop new therapeutic agents. Scorpion chloride channel toxins (ClTxs), such as Chlorotoxin selectively inhibit human Matrix Methaloproteinase-2 (hMMP-2). The inhibitors of hMMP-2 have potential use in cancer therapy. Three new ClTxs, meuCl14, meuCl15 and meuCl16, derived from the venom transcriptome of Iranian scorpion, M. eupeus (Buthidea family), show high sequence identity (71.4%) with Chlorotoxin. Here, 3-D homology model of new ClTxs were constructed. The models were optimized by Molecular Dynamics simulation based on MDFF (molecular dynamics flexible fitting) method. new ClTxs indicate the presence of CSαβ folding of other scorpion toxins. A docking followed by steered molecular dynamics (SMD) simulations to investigate the interactions of meuCl14, meuCl15 and meuCl16 with hMMP-2 was applied. The current study creates a correlation between the unbinding force and the inhibition activities of meuCl14, meuCl15 and meuCl16 to shed some insights as to which toxin may be used as a drug deliverer. To this aim, SMD simulations using Constant Force Pulling method were carried out. The SMD provided useful details related to the changes of electrostatic, van de Waals (vdW), and hydrogen-bonding (H-bonding) interactions between ligands and receptor during the pathway of unbinding. According to SMD results, the interaction of hMMP-2 with meuCl14 is more stable. In addition, Arginine residue was found to contribute significantly in interaction of ClTxs with hMMP-2. All in all, the present study is a dynamical approach whose results are capable of being implemented in structure-based drug design.