In Silico Screening of Multi-Domain Targeted Inhibitors for PTK6: A Strategy Integrating Drug Repurposing and Consensus Docking

Abstract

Protein tyrosine kinase 6 (PTK6), also known as breast tumor kinase (BRK), serves as a non-receptor intracellular tyrosine kinase within the Src kinases family. Structurally resembling other Src kinases, PTK6 possesses an Src homology 3 (SH3) domain, an Src homology 2 (SH2) domain, and a tyrosine kinase domain (SH1). While considerable efforts have been dedicated to designing PTK6 inhibitors targeting the SH1 domain, which is responsible for kinase activity in various pathways, it has been observed that solely inhibiting the SH1 domain does not effectively suppress PTK6 activity. Subsequent investigations have revealed the involvement of SH2 and SH3 domains in intramolecular and substrate binding interactions, which are crucial for PTK6 function. Consequently, the identification of PTK6 inhibitors targeting not only the SH1 domain but also the SH2 and SH3 domains becomes imperative. Through an in silico structural-based virtual screening approach, incorporating drug repurposing and a consensus docking approach, we have successfully identified four potential ligands capable of concurrently inhibiting the tyrosine kinase domain and SH2/SH3 domains of PT6K simultaneously. This finding suggests potential pathways for therapeutic interventions in PTK6 inhibition.

Keywords: PTK6; consensus docking; drug repurposing; in silico studies; structure based virtual screening.

Figure 6

Lead ligands bound to multiple domains. (A) Epirubicin bound to SH1 and SH3 domains. (B) Regoragenib bound to SH1 and SH3 domains. (C) Zafirlukast bound to SH2 and SH3 domains (D) Declatasvir bound to SH1, SH2 and SH3 domains.

Figure 1

Structure of full PTK6 protein, encompassing an Src homology 3 (SH3) domain, an Src homology 2 (SH2) domain, and a tyrosine kinase domain (SH1).

Figure 2

Structure of ligand Meloxicam docked to PTK6 kinase SH1 domain in MOE, showing CH–π interactions with Val24 and Ser90, and HB interactions with Glu84, Arg135 and Asp149.

Figure 3

Structure of lead ligand Daclatasvir bound to PTK6 kinase SH2 domain in MOE, showing HB interactions with Pro75 and Asn79.

Figure 4

The top 10 ligands identified through consensus docking.

Figure 5

Ligand Zafirlukast bound to the PTK6 kinase SH3 domain in MOE, showing CH–π interactions with Lys12 and Thr72 as well as HB interactions with Met01 and Gln06.