All the selected ligands were downloaded from your ZINC database (https://zinc

All the selected ligands were downloaded from your ZINC database ( using filters such as in-stock and drug-like, and the selection of ligands was performed based on Lipinskis rule of five (molecular excess weight limit of 300 to 600 Da, hydrogen-bond acceptor limit of 10, hydrogen-bond donor limit of 5, rotatable-bond limit of 7, and log P limit of 5). Introduction 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 name (Physique 1). The SH1 domain name (also called the catalytic domain name) is composed of two subdomains (generally termed N-terminal and C-terminal lobes) separated by a cleft. The N-terminal lobe contains the highly Ubenimex conserved hinge region that is implicated in the conversation with the ATP-adenine ring and to which most of the Src inhibitors anchor through hydrogen bonding. The C-terminal lobe is usually 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. The phosphorylation of this residue stabilizes the kinases in an active conformation accessible to ATP and substrates. On the contrary, when another tyrosine residue located in the C-terminal lobe tail (Tyr530 in human c-Src) is usually phosphorylated, a closed conformation is usually induced [3]. The SH2 and SH3 domains regulate the Src catalytic activity through both intramolecular and proteinCprotein interactions. The SH4 domain name is usually a 15-amino acid sequence whose myristoylation allows the binding of Src users to the inner surface of the plasma membrane. The unique domain is included in the N-terminal segment of the proteins, together with SH4, and is composed of 50C70 residues. Unlike the SH domains, it displays the greatest divergence among the SFKs and thus probably contributes to the differentiation of their biological functions [4]. Src is usually a central signaling hub that can be activated by many factors, including immune-response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors and cytokine receptors [5]. In normal cells, Src is only transiently activated during the multiple cellular events in Ubenimex which it is involved. Conversely, Src is usually overexpressed and/or hyperactivated in a large variety of solid tumors and is probably a strong promoting factor for the development of metastatic malignancy phenotypes [6]. Src is responsible for many human cancers such as lung [7], neuronal [8], ovarian [9], esophageal [10] and gastric cancers [11], as well as melanoma [12] and Kaposis sarcoma [13]. Due to its involvement in many cellular processes related to malignancy development, Src has long been considered a potential drug target in oncology. Open Ubenimex in a separate window Physique 1 The crystal structure of the Src kinase and Rabbit polyclonal to Cytokeratin5 schematic domain name structure. The Src inhibitors developed to date are generally categorized into three major classes: (1) tyrosine kinase activity inhibitors (ATP-competitive inhibitors); (2) proteinCprotein conversation inhibitors (SH2, SH3 or substrate-binding domain name); (3) enzyme destabilizers that provide a correlation between Src and its united molecular chaperone, i.e., warmth shock protein 90 (Hsp90) [14,15]. The search for small molecules with an inhibitory activity toward Src kinases constitutes a growing field of study. Several compounds have entered clinical trials, with two compounds ultimately approved by the FDA: dasatinib, approved in 2006, and bosutinib, approved in 2012 [16]. However, dasatinib is known to inhibit over 40 kinases, while bosutinib inhibits over 45 kinases, making it impossible to use these compounds as selective mechanistic probes for Src-dependent pharmacology [17,18]. Furthermore, most Src inhibitors reported share similar scaffolds such as pyrazolo [3,4-d] pyrimidine, quinoline and quinazoline (Physique 2). Ubenimex To this end, it is meaningful to find more effective and selective Src inhibitors with new chemical scaffolds. Open in a separate windows Physique 2 Chemical structures of previously reported Src inhibitors. In this work, we statement an integrated testing method made up of pharmacophore-based virtual testing; molecular docking; absorption, distribution, metabolism, removal and toxicity (ADMET) prediction; and molecular dynamics (MD) simulations to find novel Src inhibitors. 2. Results and Discussion 2.1. Preparation of Chemical Database Prior to performing the virtual screening, the database needed to undergo several filtering and preparation actions to reduce the enormous.

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