Molecular Dynamics and Integrated Pharmacophore-based Identification of Dual [Formula: See Text] Inhibitors

Overview

Journal Mol Divers

Date 2017 Nov 16

PMID 29138965

Citations 1

Authors

Maninder Kaur

Pankaj Kumar Singh

Manjinder Singh

Renu Bahadur

Om Silakari

Affiliations

Soon will be listed here.

Abstract

Despite increase in the understanding of the pathogenesis of rheumatoid arthritis (RA), it remains a tough challenge. The advent of kinases involved in key intracellular pathways in pathogenesis of RA may provide a new phase of drug discovery for RA. The present study is aimed to identify dual JAK3/[Formula: see text] inhibitors by developing an optimum pharmacophore model integrating the information revealed by ligand-based pharmacophore models and structure-based pharmacophore models (SBPMs). For JAK3 inhibitors, the addition of an aromatic ring feature and for [Formula: see text] the addition of a hydrophobic feature proposed by SBPMs lead to five-point pharmacophore (i.e., AADHR.54 (JAK3)) and six-point pharmacophore (i.e., AAAHRR.45 ([Formula: see text])). The obtained pharmacophores were validated and used for virtual screening and then for docking-based screening. Molecules were further evaluated for ADME properties, and their docked protein complexes were subjected to MM-GBSA energy calculations and molecular dynamic simulations. The top two hit compounds with novel scaffolds 2-oxo-1,2-dihydroquinoline and benzo[d]oxazole showed inhibitory activity for JAK3 and [Formula: see text].

Citing Articles

Pharmacoinformatics-based identification of transmembrane protease serine-2 inhibitors from Morus Alba as SARS-CoV-2 cell entry inhibitors.

Shakya A, Chikhale R, Bhat H, Ali Alasmary F, Almutairi T, Ghosh S Mol Divers. 2021; 26(1):265-278.

PMID: 33786727 PMC: 8009078. DOI: 10.1007/s11030-021-10209-3.

References

Brasca M, Nesi M, Avanzi N, Ballinari D, Bandiera T, Bertrand J . Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors. Bioorg Med Chem. 2014; 22(17):4998-5012. DOI: 10.1016/j.bmc.2014.06.025. View

Lu S, Wu J, Liu H, Zhao J, Liu K, Chuang C . The discovery of potential acetylcholinesterase inhibitors: a combination of pharmacophore modeling, virtual screening, and molecular docking studies. J Biomed Sci. 2011; 18:8. PMC: 3036604. DOI: 10.1186/1423-0127-18-8. View

Dixon S, Smondyrev A, Knoll E, Rao S, Shaw D, Friesner R . PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results. J Comput Aided Mol Des. 2006; 20(10-11):647-71. DOI: 10.1007/s10822-006-9087-6. View

Broekman F, Giovannetti E, Peters G . Tyrosine kinase inhibitors: Multi-targeted or single-targeted?. World J Clin Oncol. 2011; 2(2):80-93. PMC: 3095472. DOI: 10.5306/wjco.v2.i2.80. View

Friesner R, Banks J, Murphy R, Halgren T, Klicic J, Mainz D . Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004; 47(7):1739-49. DOI: 10.1021/jm0306430. View

Chakravarty S, Poulikakos P, Ivashkiv L, Salmon J, Kalliolias G . Kinase inhibitors: a new tool for the treatment of rheumatoid arthritis. Clin Immunol. 2013; 148(1):66-78. DOI: 10.1016/j.clim.2013.04.007. View

Harikrishnan L, Kamau M, Wan H, Inghrim J, Zimmermann K, Sang X . Pyrrolo[1,2-f]triazines as JAK2 inhibitors: achieving potency and selectivity for JAK2 over JAK3. Bioorg Med Chem Lett. 2011; 21(5):1425-8. DOI: 10.1016/j.bmcl.2011.01.022. View

Papaetis G, Syrigos K . Sunitinib: a multitargeted receptor tyrosine kinase inhibitor in the era of molecular cancer therapies. BioDrugs. 2009; 23(6):377-89. DOI: 10.2165/11318860-000000000-00000. View

Gerspacher M, Furet P, Pissot-Soldermann C, Gaul C, Holzer P, Vangrevelinghe E . 2-Amino-aryl-7-aryl-benzoxazoles as potent, selective and orally available JAK2 inhibitors. Bioorg Med Chem Lett. 2010; 20(5):1724-7. DOI: 10.1016/j.bmcl.2010.01.069. View

10.

Sutherlin D, Baker S, Bisconte A, Blaney P, Brown A, Chan B . Potent and selective inhibitors of PI3Kδ: obtaining isoform selectivity from the affinity pocket and tryptophan shelf. Bioorg Med Chem Lett. 2012; 22(13):4296-302. DOI: 10.1016/j.bmcl.2012.05.027. View

11.

Barlaam B, Cosulich S, Degorce S, Fitzek M, Giordanetto F, Green S . Discovery of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours. Bioorg Med Chem Lett. 2014; 24(16):3928-35. DOI: 10.1016/j.bmcl.2014.06.040. View

12.

Jasuja H, Chadha N, Kaur M, Silakari O . Dual inhibitors of Janus kinase 2 and 3 (JAK2/3): designing by pharmacophore- and docking-based virtual screening approach. Mol Divers. 2014; 18(2):253-67. DOI: 10.1007/s11030-013-9497-z. View

13.

Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N . Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987; 262(12):5592-5. View

14.

Chrencik J, Patny A, Leung I, Korniski B, Emmons T, Hall T . Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J Mol Biol. 2010; 400(3):413-33. DOI: 10.1016/j.jmb.2010.05.020. View

15.

Kendall J, Rewcastle G, Frederick R, Mawson C, Denny W, Marshall E . Synthesis, biological evaluation and molecular modelling of sulfonohydrazides as selective PI3K p110alpha inhibitors. Bioorg Med Chem. 2007; 15(24):7677-87. DOI: 10.1016/j.bmc.2007.08.062. View

16.

Forsyth T, Kearney P, Kim B, Johnson H, Aay N, Arcalas A . SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors. Bioorg Med Chem Lett. 2012; 22(24):7653-8. DOI: 10.1016/j.bmcl.2012.10.007. View

17.

Adams C, Aldous D, Amendola S, Bamborough P, Bright C, Crowe S . Mapping the kinase domain of Janus Kinase 3. Bioorg Med Chem Lett. 2003; 13(18):3105-10. DOI: 10.1016/s0960-894x(03)00657-7. View

18.

Thoma G, Nuninger F, Falchetto R, Hermes E, Tavares G, Vangrevelinghe E . Identification of a potent Janus kinase 3 inhibitor with high selectivity within the Janus kinase family. J Med Chem. 2010; 54(1):284-8. DOI: 10.1021/jm101157q. View

19.

Bender A, Glen R . A discussion of measures of enrichment in virtual screening: comparing the information content of descriptors with increasing levels of sophistication. J Chem Inf Model. 2005; 45(5):1369-75. DOI: 10.1021/ci0500177. View

20.

Pissot-Soldermann C, Gerspacher M, Furet P, Gaul C, Holzer P, McCarthy C . Discovery and SAR of potent, orally available 2,8-diaryl-quinoxalines as a new class of JAK2 inhibitors. Bioorg Med Chem Lett. 2010; 20(8):2609-13. DOI: 10.1016/j.bmcl.2010.02.056. View