Understanding the structural features of JAK2 inhibitors: a combined 3D-QSAR, DFT and molecular dynamics study

  • Sathya Babu
  • Santhosh Kumar Nagarajan
  • Thirumurthy MadhavanEmail author
Original Article


JAK2 plays a critical role in JAK/STAT signaling pathway and in patho-mechanism of myeloproliferative disorders and autoimmune diseases. Thus, effective JAK2 inhibitors provide a promising opportunity for the pharmaceutical intervention of many diseases. In this work, 3D-QSAR study was performed on a series of 1-amino-5H-pyrido-indole-4-carboxamide derivatives as JAK2 inhibitors to obtain reliable comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) models with three different alignment methods. Among the different alignment methods, ligand-based (CoMFA: q2 = 0.676, r2 = 0.979; CoMSIA: q2 = 0.700, r2 = 0.953) and pharmacophore-based alignment (CoMFA: q2 = 0.710, r2 = 0.982; CoMSIA: q2 = 0.686, r2 = 0.960) has produced better statistical results when compared to receptor-based alignment (CoMFA: q2 = 0.507, r2 = 0.979; CoMSIA: q2 = 0.544, r2 = 0.917). Statistical parameters indicated that data are well fitted and have high predictive ability. The presence of electrostatic and hydrophobic field is highly desirable for potent inhibitory activity, and the steric field plays a minor role in modulating the activity. The contour analysis indicates ARG980, ASN981, ASP939 and LEU937 have more possibility of interacting with bulky, hydrophobic groups in pyrido and positive and negative groups in pyrazole ring. Based on our findings, we have designed sixteen molecules and predicted its activity and drug-like properties. Subsequently, molecular docking, molecular dynamics and DFT calculations were performed to evaluate its potency.

Graphical abstract


JAK2 3D-QSAR CoMFA CoMSIA Molecular dynamics DFT 



This research was supported by Start-Up Research Grant for Young Scientist (SB/YS/LS-128/2013), funded by the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India. Author SB thanks CSIR, New Delhi, India for providing Senior Research Fellowship (SRF).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11030_2018_9913_MOESM1_ESM.docx (1.1 mb)
Supplementary material 1 (DOCX 1156 kb)


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Authors and Affiliations

  1. 1.Computational Biology Lab, Department of Genetic Engineering, School of BioengineeringSRM Institute of Science and TechnologyChennaiIndia

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