Exploring molecular interactions of potential inhibitors against the spleen tyrosine kinase implicated in autoimmune disorders via virtual screening and molecular dynamics simulations.

Abstract

The spleen tyrosine kinase (Syk) plays a pivotal role in immune cells' signal transduction mechanism. While fostamatinib, an FDA-approved Syk inhibitor, is currently used to treat immune thrombocytopenia, the search for improved Syk-targeted medications to treat autoimmune diseases is still underway. Herein, we screened 38,493 compounds against Syk and selected eight leads based on the docking score and ADMET properties, and performed 3$\times$200 ns long molecular dynamics simulations of the apo and Syk-ligand complexes. We considered R406, the active component of fostamatinib, as a control. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations demonstrated the lead1 ($\Delta G_{bind}$ = -30.35 kcal/mol) exhibited a similar binding free energy as the control ($\Delta G_{bind}$= -29.82 kcal/mol). The Syk stabilizing effect of lead1 was also indicated in its network features, sampling space, and residual correlation motion analysis. We further generated 100 structural analogues of lead1 using deep learning, and one of the analogues displayed a better binding free energy ($\Delta G_{bind}$= -47.58 kcal/mol) compared to the control or lead1, facilitated by more favourable van der Waals interactions and lesser binding-opposing net polar forces. This analogue may be further exploited to develop effective therapeutics against Syk-associated diseases after validation in vitro and in vivo.