title: Identification of new dual spleen tyrosine kinase (Syk) and phosphoionositide-3-kinase δ (PI3Kδ) inhibitors using ligand and structure-based integrated ideal pharmacophore models.
abstract: Owing to the complex pathophysiology of autoimmune disorders, it is very challenging to develop successful treatment strategies. Single-target agents are not desired therapeutics for such multi-factorial disorders. Considering the current need for the treatment of complex autoimmune disorders, dual inhibitors of Syk and PI3Kδ have been designed using ligand and structure-based molecular modelling strategies. In the present work, structure and ligand-based pharmacophore modelling was implemented for a varied set of Syk and PI3Kδ inhibitors. Ligand-based pharmacophore models (LBPMs) were developed for two kinases: ADPR.14 (r(2)train = 0.809) for Syk, comprising one hydrogen bond acceptor, one hydrogen bond donor, one positive ionisable and one ring aromatic feature, and for PI3Kδ: AAARR.45 (r(2)train = 0.942) consisting of three hydrogen bond acceptor and two ring aromatic features. The generated e-pharmacophore models revealed an additional ring aromatic and hydrophobic feature important for Syk and PI3Kδ inhibition, respectively. Subsequently, LBPMs were modified resulting in APDRR.14 hypothesis for Syk inhibitors and AAAHRR.45 hypothesis for PI3Kδ inhibitors employed for virtual screening. Thus, the combination of ligand and structure-based pharmacophore modelling helped in developing ideal pharmacophore models that may be an efficient tool for the designing of novel dual inhibitors of Syk and PI3Kδ.
authors.affiliation: a Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research , Punjabi University , Patiala , India.
authors.forename: M
authors.initials: M
authors.lastname: Kaur
authors.affiliation: a Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research , Punjabi University , Patiala , India.
authors.forename: O
authors.initials: O
authors.lastname: Silakari
mesh_terms: D001327:Autoimmune Diseases / Q000188:drug therapy; D062126:Databases, Chemical; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D000072377:Syk Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D008024:Ligands; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D000072377:Syk Kinase
keywords: B-cell signalling; Spleen tyrosine kinase (Syk); autoimmune disorders; e-pharmacophore; phosphoionositide-3-kinase δ (PI3Kδ)