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

Abstract

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

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Acknowledgements

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).

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Correspondence to Thirumurthy Madhavan.

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Babu, S., Nagarajan, S.K. & Madhavan, T. Understanding the structural features of JAK2 inhibitors: a combined 3D-QSAR, DFT and molecular dynamics study. Mol Divers 23, 845–874 (2019). https://doi.org/10.1007/s11030-018-09913-4

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Keywords

  • JAK2
  • 3D-QSAR
  • CoMFA
  • CoMSIA
  • Molecular dynamics
  • DFT