Abstract
Src plays a crucial role in many signaling pathways and contributes to a variety of cancers. Therefore, Src has long been considered an attractive drug target in oncology. However, the development of Src inhibitors with selectivity and novelty has been challenging. In the present study, pharmacophore-based virtual screening and molecular docking were carried out to identify potential Src inhibitors. A total of 891 molecules were obtained after pharmacophore-based virtual screening, and 10 molecules with high docking scores and strong interactions were selected as potential active molecules for further study. Absorption, distribution, metabolism, elimination and toxicity (ADMET) property evaluation was used to ascertain the drug-like properties of the obtained molecules. The proposed inhibitor–protein complexes were further subjected to molecular dynamics (MD) simulations involving root-mean-square deviation and root-mean-square fluctuation to explore the binding mode stability inside active pockets. Finally, two molecules (ZINC3214460 and ZINC1380384) were obtained as potential lead compounds against Src kinase. All these analyses provide a reference for the further development of novel Src inhibitors.
Highlights
The Src family kinases (SFKs) are a family of non-receptor tyrosine kinases, which are involved in a wide variety of essential functions to sustain cellular homeostasis, where they regulate cell cycle progression, motility, proliferation, differentiation and survival, among other cellular processes [1].As a prototypical member of the SFKs, Src contains Yes, Fyn, Lyn, Lck, Hck, Fgr, Yrk, Frk and Blk kinases [2]
The N-terminal lobe contains the highly conserved hinge region that is implicated in the interaction with the ATP-adenine ring and to which most of the Src inhibitors anchor through hydrogen bonding
We report an integrated screening method containing pharmacophore-based virtual screening; molecular docking; absorption, distribution, metabolism, elimination and toxicity (ADMET)
Summary
The Src family kinases (SFKs) are a family of non-receptor tyrosine kinases, which are involved in a wide variety of essential functions to sustain cellular homeostasis, where they regulate cell cycle progression, motility, proliferation, differentiation and survival, among other cellular processes [1]. As a prototypical member of the SFKs, Src contains Yes, Fyn, Lyn, Lck, Hck, Fgr, Yrk, Frk and Blk kinases [2]. Src consists of four homology domains (SH1, SH2, SH3 and SH4) and a unique domain (Figure 1). The C-terminal lobe is larger, comprises an activation loop that contains a tyrosine residue that can be autophosphorylated (Tyr419 in human c-Src) and is the positive regulatory site responsible for maximizing kinase activity
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