3D pharmacophore modeling and docking studies of 1-amino-5H-pyrido [4, 3-b] indol-4-carboxamide inhibitors of Janus Kinase 2(JAK2)

Ramesh Itteboina; Srilata Ballu; Sree Kanth Sivan; Sailu Pathkala; Vijjulatha Manga

Authors

Ramesh Itteboina Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad – 07, India
Srilata Ballu Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad – 07, India
Sree Kanth Sivan Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad – 07, India
Sailu Pathkala Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad – 07, India
Vijjulatha Manga Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad – 07, India

Keywords:

3D QSAR (3 dimensional quantitative structure activity relationship), GLIDE (Grid-based ligand docking with energies), STAT (signal Transducers and activators of tran-scription), Standard precision (SP), Extra precision (XP)

Abstract

Janus kinase 2(JAK2) is an intracellular nonreceptor tyrosine kinase that belongs to the JAK family. JAK-signal transducer and activator of transcription (JAK-STAT) pathway mediate signaling by cytokines, which control survival, proliferation and differentiation of a variety of cells. Docking studies were performed using GLIDE (Grid-based ligand docking with energies) on JAK 2 protein (PDB. id 3RVG) that was retrieved from protein data bank, here standard precision (SP) and extra precision (XP) docking protocols have been adopted. Pharmacophore based 3D- QSAR analysis was performed on a series of 1- Amino-5H-Pyrido [4, 3-b] Indole-4- Carboxamide reported as inhibitors of JAK2 Activity. Five point Pharmacophore with one hydrogen bond acceptor (A), Three hydrogen bond donor (D), and one hydrophobic group (H), as Pharmocophoric features were developed. The Pharmacophore hypothesis ADDDH yielded a statistically significant 3D-QSAR model with 0.962 as R² value and 0.688 as Q² value. The developed Pharmacophore model was validated by predicting the activity of test set molecules. The squared predicted correlation coefficient of 0.70(R²_Pred) was observed between experimental and predicted activity values of test set molecules. Further molecular docking studies were carried out to understand the binding mode of these inhibitors with the receptor. The results obtained from 3D-QSAR and docking studies were used for rational design of potent inhibitors against JAK2.