Potential Inhibitors of Fascin From A Database of Marine Natural Products: A Virtual Screening and Molecular Dynamics Study.

Lirui Lin,Kai Lin,Yinwei Cheng,Xiaodong Wu,Li-Yan Xu,En-Min Li,Geng Dong,Jia Liu

doi:10.3389/fchem.2021.719949

Abstract

Marine nature products are unique compounds that are produced by the marine environment including plants, animals, and microorganisms. The wide diversity of marine natural products have great potential and are versatile in terms of drug discovery. In this paper, we use state-of-the-art computational methods to discover inhibitors from marine natural products to block the function of Fascin, an overexpressed protein in various cancers. First, virtual screening (pharmacophore model and molecular docking) was carried out based on a marine natural products database (12015 molecules) and provided eighteen molecules that could potentially inhibit the function of Fascin. Next, molecular mechanics generalized Born surface area (MM/GBSA) calculations were conducted and indicated that four molecules have higher binding affinities than the inhibitor NP-G2-029, which was validated experimentally. ADMET analyses of pharmacokinetics demonstrated that one of the four molecules does not match the criterion. Finally, ligand Gaussian accelerated molecular dynamics (LiGaMD) simulations were carried out to validate the three inhibitors binding to Fascin stably. In addition, dynamic interactions between protein and ligands were analyzed systematically. Our study will accelerate the development of the cancer drugs targeting Fascin.

Highlights

With a deeper understanding of the particularity of the marine environment and the diversity of marine biology, researchers have developed many applications based on aquatic and marine resources (Carroll et al, 2021)
Because no complex structures were solved for the NP-G2-044, -112, and -113, complex structures were prepared by molecular docking
The pharmacophore virtual screening was performed on the 12,015 compounds (Figure 3)

Summary

Introduction

With a deeper understanding of the particularity of the marine environment and the diversity of marine biology, researchers have developed many applications based on aquatic and marine resources (Carroll et al, 2021). In the metabolism of marine organisms, enormous and innovative marine natural products (MNPs) are produced, and those products can be exploited to develop new functional materials and drugs (Barbosa and Roque, 2019). To exploit the data of MNPs for the treatment of diseases conveniently, some databases of MNPs are built for drug screening and other research on ocean resources (Haroun et al, 2019). Cell invasion and migration are essential features of tumor cells and actin cytoskeleton reconstruction triggers the switch of protrusive tissue, e.g., filopodia, lamellipodia, and lamellipodia (Machesky and Li, 2010). Fascin plays a key role in the formation of filopodia, which leads to increased cell movability in multiple transformed cells (Conesa-Zamora et al, 2013; Tan et al, 2013). Some studies have indicated that Fascin can be used as a diagnostic marker and therapeutic target for aggressive tumors (Tan et al, 2013; Rodrigues et al, 2017)

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Conclusion