Molecular Dynamics Simulation-Driven Focused Virtual Screening and Experimental Validation of Inhibitors for MTDH-SND1 Protein–Protein Interaction

• DOI: 10.1021/acs.jcim.3c00310
• Publication Date: 2023-05-25T08:37:20Z
• Authors: Yadi Xu; Xiaoyu Guo; Dengjie Yan; Xihan Dang; Li Guo; Tao Jia; Qiantao Wang
• Keywords: Dynamics

Protein–protein interactions (PPIs), in general, are attractive yet challenging drug targets. As a typical PPI, MTDH-SND1 interaction has recently been reported to be promising target malignant breast cancer and other types. However, the lack of well-defined deep pockets on interface makes it tough for rational discovery attempts. To address this issue, study, long time-scale molecular dynamics (MD) simulation-driven focused screening strategy was proposed reported. A total 12 virtual hits were purchased tested SPR assay, yielding 10 SND1 binders with micromolar or less affinities. an example, compound L5, second best hit KD 2.64 μM, further assayed MDA-MB-231 cells, showing antiproliferation IC50 value 57 μM CCK8 assay dampened interruption between MTDH proteins detected by immunofluorescence colocalization imaging. most potent small molecule inhibitor class so far, our preliminary study combining simulation vitro cellular functional evidence indicates L5 could serve as lead future optimization pharmacologic studies, MD-driven useful PPI