Exploring the Structural Dynamics of SRPK1 to Identify Competitive Inhibitors via Molecular Modeling Techniques

Upregulation of serine arginine protein kinase 1 (SRPK1), a protein responsible for phosphorylation of Ser-Arg rich residues aimed at SR proteins, is associated with apoptosis, poor survival, etc. Catalytic sites of the kinase proteins are incompetently preserved, causing difficulty in developing competitive inhibitors for ATP binding sites with broad selectivity; hence, search for inhibitor for the ATP binding pocket of SRPK1 is a necessity for medication against carcinogenesis. Natural product database is explored, and six small molecules are identified; having tolerable pharmacokinetics (low blood brain barrier, moderate clearance rate etc.) and quantum chemical properties are checked. Molecular docking study followed by molecular dynamics give insights into the effective interactions at the ATP pocket. Ligands are screened by MM-GBSA/NMA protocol, followed by estimation of unbinding potential of mean force (PMF) using well-tempered metadynamics. Well-tempered metadynamics confirmed unbinding PMF of -23.71 kcal mol^-1 for CNP0199214 and -14.81 kcal mol^-1 for MSC1186 (Lig_ref) to a relative difference in PMF of the screened ligand to be ≈7 kcal mol^-1. A probable gating mechanism is observed for the reference ligand (Lig_ref) at the protein interface resulting multiple minima in PMF, whereas Lig_4 (CNP0199214) exhibits greater affinity toward the active pocket and therefore choice for a potent compound.