3D-QSAR, docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors
Janus kinase 3 (JAK3) is a promising drug target for the treatment of inflammatory diseases, autoimmune disorders, organ transplant rejection and various cancers. In the present study, 3D-QSAR, docking, MD simulation and MM/PBSA studies were performed on a series of pyrimidine-based JAK3 inhibitors....
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Arabian Journal of Chemistry |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878535217301788 |
| _version_ | 1828493968408576000 |
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| author | Anand Balupuri Pavithra K. Balasubramanian Seung Joo Cho |
| author_facet | Anand Balupuri Pavithra K. Balasubramanian Seung Joo Cho |
| author_sort | Anand Balupuri |
| collection | DOAJ |
| description | Janus kinase 3 (JAK3) is a promising drug target for the treatment of inflammatory diseases, autoimmune disorders, organ transplant rejection and various cancers. In the present study, 3D-QSAR, docking, MD simulation and MM/PBSA studies were performed on a series of pyrimidine-based JAK3 inhibitors. A reliable COMSIA (q2 = 0.717 and r2 = 0.986) model was developed and validated using external validation test set, bootstrapping, progressive scrambling and rm2 metrics analyses. Structural requirements identified through contour maps of the model were strategically utilized to computationally design 170 novel JAK3 inhibitors with improved potency. Docking studies were performed on the selected data set and newly designed compounds to show their binding mode and to identify important interacting residues inside the active site of JAK3. In addition, docking results of the selected designed compounds inside the active sites of JAK1, JAK2 and TYK2 indicated their JAK3 selectivity. MD simulation (100 ns) on the docked complex of compound 28 (one of highly active compounds of the data set) assisted in the further exploration of the binding interactions. Some crucial residues like Lys830 (glycine-rich loop), Val836, Ala853, Leu905 (hinge region), Cys909, Asn954, Leu956 and Ala966 were identified. Hydrogen bond interactions with hinge residue Leu905 were critical for the binding of JAK3 inhibitors. Additionally, MM/PBSA calculation provided the binding free energy of the compound 28. Newly designed molecules showed promising results in the preliminary in silico ADMET evaluations. Outcomes of the study can further be exploited to develop potent JAK3 inhibitors. Keywords: 3D-QSAR, ADMET, Docking, MD simulation, MM/PBSA |
| first_indexed | 2024-12-11T11:48:00Z |
| format | Article |
| id | doaj.art-aa53bf771c2f476eaee2b1701412a8a7 |
| institution | Directory Open Access Journal |
| issn | 1878-5352 |
| language | English |
| last_indexed | 2024-12-11T11:48:00Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Arabian Journal of Chemistry |
| spelling | doaj.art-aa53bf771c2f476eaee2b1701412a8a72022-12-22T01:08:26ZengElsevierArabian Journal of Chemistry1878-53522020-01-01131105210783D-QSAR, docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitorsAnand Balupuri0Pavithra K. Balasubramanian1Seung Joo Cho2Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju 501-759, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 305-764, Republic of KoreaDepartment of Biomedical Sciences, College of Medicine, Chosun University, Gwangju 501-759, Republic of KoreaDepartment of Biomedical Sciences, College of Medicine, Chosun University, Gwangju 501-759, Republic of Korea; Department of Cellular and Molecular Medicine, College of Medicine, Chosun University, Gwangju 501-759, Republic of Korea; Corresponding author at: College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju 501-759, Republic of Korea.Janus kinase 3 (JAK3) is a promising drug target for the treatment of inflammatory diseases, autoimmune disorders, organ transplant rejection and various cancers. In the present study, 3D-QSAR, docking, MD simulation and MM/PBSA studies were performed on a series of pyrimidine-based JAK3 inhibitors. A reliable COMSIA (q2 = 0.717 and r2 = 0.986) model was developed and validated using external validation test set, bootstrapping, progressive scrambling and rm2 metrics analyses. Structural requirements identified through contour maps of the model were strategically utilized to computationally design 170 novel JAK3 inhibitors with improved potency. Docking studies were performed on the selected data set and newly designed compounds to show their binding mode and to identify important interacting residues inside the active site of JAK3. In addition, docking results of the selected designed compounds inside the active sites of JAK1, JAK2 and TYK2 indicated their JAK3 selectivity. MD simulation (100 ns) on the docked complex of compound 28 (one of highly active compounds of the data set) assisted in the further exploration of the binding interactions. Some crucial residues like Lys830 (glycine-rich loop), Val836, Ala853, Leu905 (hinge region), Cys909, Asn954, Leu956 and Ala966 were identified. Hydrogen bond interactions with hinge residue Leu905 were critical for the binding of JAK3 inhibitors. Additionally, MM/PBSA calculation provided the binding free energy of the compound 28. Newly designed molecules showed promising results in the preliminary in silico ADMET evaluations. Outcomes of the study can further be exploited to develop potent JAK3 inhibitors. Keywords: 3D-QSAR, ADMET, Docking, MD simulation, MM/PBSAhttp://www.sciencedirect.com/science/article/pii/S1878535217301788 |
| spellingShingle | Anand Balupuri Pavithra K. Balasubramanian Seung Joo Cho 3D-QSAR, docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors Arabian Journal of Chemistry |
| title | 3D-QSAR, docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors |
| title_full | 3D-QSAR, docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors |
| title_fullStr | 3D-QSAR, docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors |
| title_full_unstemmed | 3D-QSAR, docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors |
| title_short | 3D-QSAR, docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors |
| title_sort | 3d qsar docking molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel jak3 inhibitors |
| url | http://www.sciencedirect.com/science/article/pii/S1878535217301788 |
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