In silico design of new MPS1 inhibitors via a validated structure-based virtual
screening approach

Mohammad A. Ghattas; Mohammad Al Sorkhy; Noor Atatreh

Abstract

In silico design of new MPS1 inhibitors via a validated structure-based virtual screening approach

Author(s): Mohammad A. Ghattas, Mohammad Al Sorkhy and Noor Atatreh

Cell cycle is a highly coordinated and well conserved process and abrogation in the cell cycle are a hallmark of many types of cancer, thus,it has been under the spotlight as a target of anti-cancer therapeutics for decades. A wide range of tumor-associated mutations have been linked to abnormal regulation of protein kinases. MPS1 protein family isdual-specific protein kinases among several that are heavily involved in cell cycle regulation, abrogation in MPS1 have been linked to many types of cancer. Targeting MPS1 by small molecule inhibitors has attracted many researches due to their high involvement in cancer progression. However, despite numerous trials, MPS1 inhibitors failed to reach clinical trials. In this work, we studied the protein-ligand interactions via an automated approach. At least one interaction with the MPS1 hinge region was found to be key for protein ligand binding and was used as basis for creating pharmacophoric docking constraints. Several docking protocols, e.g. standard and constrained docking protocols, were examined for their MPS1 virtual screens’ enrichment. It was found that constrained docking followed by refinement step had the superiority over other examined docking protocols. Accordingly, virtual screening for druglike library was pursued. Several hits were nominated for in vitro testing in the future as they showed convenient binding modes with the MPS1 pocket, in particular, satisfying the key interactions with the MPS1 hinge region.The knowledge-based drug design strategy explored and conducted here can potentially inform new MPS1 inhibitors.

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