Discovery of lupus nephritis targeted inhibitors based on De novo molecular design: comprehensive application of vinardo scoring, ADMET analysis, and molecular dynamics simulation

References

• Abraham, M., Alekseenko, A., Bergh, C., Blau, C., Briand, E., Doijade, M., Fleischmann, S., Gapsys, V., Garg, G., Gorelov, S., Gouaillardet, G., Gray, A., Irrgang, M. E., Jalalypour, F., Jordan, J., Junghans, C., Kanduri, P., Keller, S., Kutzner, C., … Lindahl, E. (2023). GROMACS 2023.3 Source code. https://doi.org/10.5281/ZENODO.10017686
   Google Scholar
• Anders, H.-J., Saxena, R., Zhao, M.-H., Parodis, I., Salmon, J. E., & Mohan, C. (2020). Lupus nephritis. Nature Reviews Disease Primers, 6(1), 7. https://doi.org/10.1038/s41572-019-0141-9
   PubMed Web of Science ®Google Scholar
• Aoki, T., Hiura, F., Li, A., Yang, N., Takakura-Hino, N., Mukai, S., Matsuda, M., Nishimura, F., & Jimi, E. (2023). Inhibition of non-canonical NF-κB signaling suppresses periodontal inflammation and bone loss. Frontiers in Immunology, 14, 1179007. https://doi.org/10.3389/fimmu.2023.1179007
   PubMed Web of Science ®Google Scholar
• Arshia, A. H., Shadravan, S., Solhjoo, A., Sakhteman, A., & Sami, A. (2021). De novo design of novel protease inhibitor candidates in the treatment of SARS-CoV-2 using deep learning, docking, and molecular dynamic simulations. Computers in Biology and Medicine, 139, 104967. https://doi.org/10.1016/j.compbiomed.2021.104967
   PubMed Web of Science ®Google Scholar
• Bai, Q., Tan, S., Xu, T., Liu, H., Huang, J., & Yao, X. (2021). MolAICal: A soft tool for 3D drug design of protein targets by artificial intelligence and classical algorithm. Briefings in Bioinformatics, 22(3), bbaa161. https://doi.org/10.1093/bib/bbaa161
   PubMed Web of Science ®Google Scholar
• Baskaran, Y., Ang, K. C., Anekal, P. V., Chan, W. L., Grimes, J. M., Manser, E., & Robinson, R. C. (2015). An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1. Nature Communications, 6(1), 8681. https://doi.org/10.1038/ncomms9681
   PubMedGoogle Scholar
• Bateman, A., Martin, M.-J., Orchard, S., Magrane, M., Ahmad, S., Alpi, E., Bowler-Barnett, E. H., Britto, R., Bye-A-Jee, H., Cukura, A., Denny, P., Dogan, T., Ebenezer, T., Fan, J., Garmiri, P., Da Costa Gonzales, L. J., Hatton-Ellis, E., Hussein, A., Ignatchenko, A., … Zhang, J, The UniProt Consortium. (2023). UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Research, 51, D523–D531. https://doi.org/10.1093/nar/gkac1052
   PubMed Web of Science ®Google Scholar
• Brightbill, H. D., Suto, E., Blaquiere, N., Ramamoorthi, N., Sujatha-Bhaskar, S., Gogol, E. B., Castanedo, G. M., Jackson, B. T., Kwon, Y. C., Haller, S., Lesch, J., Bents, K., Everett, C., Kohli, P. B., Linge, S., Christian, L., Barrett, K., Jaochico, A., Berezhkovskiy, L. M., … Ghilardi, N. (2018). NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus. Nature Communications, 9(1), 179. https://doi.org/10.1038/s41467-017-02672-0
   PubMedGoogle Scholar
• Cheng, J., Feng, X., Li, Z., Zhou, F., Yang, J.-M., & Zhao, Y. (2021). Pharmacological inhibition of NF-κB-inducing kinase (NIK) with small molecules for the treatment of human diseases. RSC Medicinal Chemistry, 12(4), 552–565. https://doi.org/10.1039/D0MD00361A
   PubMedGoogle Scholar
• Colovos, C., & Yeates, T. O. (1993). Verification of protein structures: Patterns of nonbonded atomic interactions. Protein Science, 2(9), 1511–1519. https://doi.org/10.1002/pro.5560020916
   PubMed Web of Science ®Google Scholar
• Eberhardt, J., Santos-Martins, D., Tillack, A. F., & Forli, S. (2021). AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. Journal of Chemical Information and Modeling, 61(8), 3891–3898. https://doi.org/10.1021/acs.jcim.1c00203
   PubMed Web of Science ®Google Scholar
• Edgar, R. C., & Batzoglou, S. (2006). Multiple sequence alignment. Current Opinion in Structural Biology, 16(3), 368–373. https://doi.org/10.1016/j.sbi.2006.04.004
   PubMed Web of Science ®Google Scholar
• Fang, L., Vilas-Boas, J., Chakraborty, S., Potter, Z. E., Register, A. C., Seeliger, M. A., & Maly, D. J. (2020). How ATP-Competitive Inhibitors Allosterically Modulate Tyrosine Kinases That Contain a Src-like Regulatory Architecture. ACS Chemical Biology, 15(7), 2005–2016. https://doi.org/10.1021/acschembio.0c00429
   PubMed Web of Science ®Google Scholar
• Fusco, A. J., Mazumder, A., Wang, V. Y.-F., Tao, Z., Ware, C., & Ghosh, G. (2016). The NF-κB subunit RelB controls p100 processing by competing with the kinases NIK and IKK1 for binding to p100. Science Signaling, 9(447), ra96. https://doi.org/10.1126/scisignal.aad9413
   PubMed Web of Science ®Google Scholar
• Gardam, S., & Brink, R. (2014). Non-Canonical NF-κB Signaling Initiated by BAFF Influences B Cell Biology at Multiple Junctures. Frontiers in Immunology, 4, 509. https://doi.org/10.3389/fimmu.2013.00509
   PubMed Web of Science ®Google Scholar
• Haselager, M. V., & Eldering, E. (2022). The Therapeutic Potential of Targeting NIK in B Cell Malignancies. Frontiers in Immunology, 13, 930986. https://doi.org/10.3389/fimmu.2022.930986
   PubMedGoogle Scholar
• Hayden, M. S., & Ghosh, S. (2008). Shared Principles in NF-κB Signaling. Cell, 132(3), 344–362. https://doi.org/10.1016/j.cell.2008.01.020
   PubMed Web of Science ®Google Scholar
• Humphrey, W., Dalke, A., & Schulten, K. (1996). VMD: Visual molecular dynamics. Journal of Molecular Graphics, 14(1), 33–38. 27–28. https://doi.org/10.1016/0263-7855(96)00018-5
   PubMedGoogle Scholar
• Jourde-Chiche, N., Whalen, E., Gondouin, B., Speake, C., Gersuk, V., Dussol, B., Burtey, S., Pascual, V., Chaussabel, D., & Chiche, L. (2017). Modular transcriptional repertoire analyses identify a blood neutrophil signature as a candidate biomarker for lupus nephritis. Rheumatology (Oxford, England), 56(3), 477–487. https://doi.org/10.1093/rheumatology/kew439
   PubMed Web of Science ®Google Scholar
• Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J., & Bolton, E. E. (2023). PubChem 2023 update. Nucleic Acids Research, 51(D1), D1373–D1380. https://doi.org/10.1093/nar/gkac956
   PubMed Web of Science ®Google Scholar
• Koes, D. R., Baumgartner, M. P., & Camacho, C. J. (2013). Lessons learned in empirical scoring with smina from the CSAR 2011 benchmarking exercise. Journal of Chemical Information and Modeling, 53(8), 1893–1904. https://doi.org/10.1021/ci300604z
   PubMed Web of Science ®Google Scholar
• Li, M., Rehman, A. U., Liu, Y., Chen, K., & Lu, S. (2021). Dual roles of ATP-binding site in protein kinases: Orthosteric inhibition and allosteric regulation. Adv Protein Chem Struct Biol, 124, 87–119. https://doi.org/10.1016/bs.apcsb.2020.09.005
   PubMed Web of Science ®Google Scholar
• Li, N. L., Birmingham, D. J., & Rovin, B. H. (2021). Expanding the Role of Complement Therapies: The Case for Lupus Nephritis. Journal of Clinical Medicine, 10(4), 626. https://doi.org/10.3390/jcm10040626
   PubMed Web of Science ®Google Scholar
• Lu, T., & Chen, F. (2012). Multiwfn: A multifunctional wavefunction analyzer. Journal of Computational Chemistry, 33(5), 580–592. https://doi.org/10.1002/jcc.22885
   PubMed Web of Science ®Google Scholar
• Lucas, J. E., & Kortemme, T. (2020). New computational protein design methods for de novo small molecule binding sites. PLoS Computational Biology, 16(10), e1008178. https://doi.org/10.1371/journal.pcbi.1008178
   PubMed Web of Science ®Google Scholar
• Mazzera, L., Abeltino, M., Lombardi, G., Cantoni, A. M., Ria, R., Ricca, M., Saltarella, I., Naponelli, V., Rizzi, F. M. A., Perris, R., Corradi, A., Vacca, A., Bonati, A., & Lunghi, P. (2019). Functional interplay between NF-κB-inducing kinase and c-Abl kinases limits response to Aurora inhibitors in multiple myeloma. Haematologica, 104(12), 2465–2481. https://doi.org/10.3324/haematol.2018.208280
   PubMed Web of Science ®Google Scholar
• Merk, D., Friedrich, L., Grisoni, F., & Schneider, G. (2018). De Novo Design of Bioactive Small Molecules by Artificial Intelligence. Mol Inform, 37(1-2), 1700153. https://doi.org/10.1002/minf.201700153
   PubMed Web of Science ®Google Scholar
• Meyers, J., Fabian, B., & Brown, N. (2021). De novo molecular design and generative models. Drug Discovery Today. 26(11), 2707–2715. https://doi.org/10.1016/j.drudis.2021.05.019
   PubMed Web of Science ®Google Scholar
• Mishra, P., & Günther, S. (2018). New insights into the structural dynamics of the kinase JNK3. Scientific Reports, 8(1), 9435. https://doi.org/10.1038/s41598-018-27867-3
   PubMedGoogle Scholar
• Möckel, T., Basta, F., Weinmann-Menke, J., & Schwarting, A. (2021). B cell activating factor (BAFF): Structure, functions, autoimmunity and clinical implications in Systemic Lupus Erythematosus (SLE). Autoimmunity Reviews, 20(2), 102736. https://doi.org/10.1016/j.autrev.2020.102736
   PubMed Web of Science ®Google Scholar
• Mohan, C., Zhang, T., & Putterman, C. (2023). Pathogenic cellular and molecular mediators in lupus nephritis. Nature Reviews. Nephrology, 19(8), 491–508. https://doi.org/10.1038/s41581-023-00722-z
   PubMed Web of Science ®Google Scholar
• Neese, F., Wennmohs, F., Becker, U., & Riplinger, C. (2020). The ORCA quantum chemistry program package. The Journal of Chemical Physics, 152(22), 224108. https://doi.org/10.1063/5.0004608
   PubMed Web of Science ®Google Scholar
• Noetzlin, S., Breville, G., Seebach, J. D., & Gastaldi, G. (2022). Short-term glucocorticoid-related side effects and adverse reactions: A narrative review and practical approach. Swiss Medical Weekly, 152(0102), w30088. https://doi.org/10.4414/smw.2022.w30088
   PubMedGoogle Scholar
• Özçelik, R., van Tilborg, D., Jiménez-Luna, J., & Grisoni, F. (2022). Structure-based drug discovery with deep learning, http://arxiv.org/abs/2212.13295 (accessed November 26, 2023).
   Google Scholar
• Papaleo, E., Mereghetti, P., Fantucci, P., Grandori, R., & De Gioia, L. (2009). Free-energy landscape, principal component analysis, and structural clustering to identify representative conformations from molecular dynamics simulations: The myoglobin case. Journal of Molecular Graphics & Modelling, 27(8), 889–899. https://doi.org/10.1016/j.jmgm.2009.01.006
   PubMed Web of Science ®Google Scholar
• Pflug, K. M., & Sitcheran, R. (2020). Targeting NF-κB-Inducing Kinase (NIK) in Immunity, Inflammation, and Cancer. International Journal of Molecular Sciences, 21(22), 8470. https://doi.org/10.3390/ijms21228470
   PubMed Web of Science ®Google Scholar
• Polizzi, N. F., & DeGrado, W. F. (2020). A defined structural unit enables de novo design of small-molecule-binding proteins. Science (New York, N.Y.), 369(6508), 1227–1233. https://doi.org/10.1126/science.abb8330
   PubMed Web of Science ®Google Scholar
• Quiroga, R., & Villarreal, M. A. (2016). Vinardo: A Scoring Function Based on Autodock Vina Improves Scoring, Docking, and Virtual Screening. PLoS One. 11(5), e0155183. https://doi.org/10.1371/journal.pone.0155183
   PubMed Web of Science ®Google Scholar
• Reinhardt, R., & Leonard, T. A. (2023). A critical evaluation of protein kinase regulation by activation loop autophosphorylation. Elife, 12, e88210. https://doi.org/10.7554/eLife.88210
   PubMed Web of Science ®Google Scholar
• Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015). limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Research, 43(7), e47–e47–e47. https://doi.org/10.1093/nar/gkv007
   Web of Science ®Google Scholar
• Robert, X., & Gouet, P. (2014). Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Research, 42(Web Server issue), W320–W324. https://doi.org/10.1093/nar/gku316
   PubMed Web of Science ®Google Scholar
• Schauperl, M., Nerenberg, P. S., Jang, H., Wang, L.-P., Bayly, C. I., Mobley, D. L., & Gilson, M. K. (2020). Non-bonded force field model with advanced restrained electrostatic potential charges (RESP2). Communications Chemistry, 3(1), 44. https://doi.org/10.1038/s42004-020-0291-4
   PubMed Web of Science ®Google Scholar
• Siu, J. H. Y., Pitcher, M. J., Tull, T. J., Velounias, R. L., Guesdon, W., Montorsi, L., Mahbubani, K. T., Ellis, R., Dhami, P., Todd, K., Kadolsky, U. D., Kleeman, M., D'Cruz, D. P., Saeb-Parsy, K., Bemark, M., Pettigrew, G. J., & Spencer, J. (2022). Two subsets of human marginal zone B cells resolved by global analysis of lymphoid tissues and blood. Science Immunology, 7(69), eabm9060. https://doi.org/10.1126/sciimmunol.abm9060
   PubMed Web of Science ®Google Scholar
• Su, M., Yang, Q., Du, Y., Feng, G., Liu, Z., Li, Y., & Wang, R. (2019). Comparative Assessment of Scoring Functions: The CASF-2016 Update. Journal of Chemical Information and Modeling, 59(2), 895–913. https://doi.org/10.1021/acs.jcim.8b00545
   PubMed Web of Science ®Google Scholar
• Sun, S.-C. (2011). Non-canonical NF-κB signaling pathway. Cell Research, 21(1), 71–85. https://doi.org/10.1038/cr.2010.177
   PubMed Web of Science ®Google Scholar
• Suso, J. P., Posso-Osorio, I., Jiménez, C. A., Naranjo-Escobar, J., Ospina, F. E., Sánchez, A., Cañas, C. A., & Tobón, G. J. (2018). Profile of BAFF and its receptors’ expression in lupus nephritis is associated with pathological classes. Lupus, 27(5), 708–715. https://doi.org/10.1177/0961203317739132
   PubMed Web of Science ®Google Scholar
• Tang, Y. (2023). Analysis of the binding pattern of NIK inhibitors by computational simulation. Journal of Biomolecular Structure & Dynamics, 2023, 1–14. https://doi.org/10.1080/07391102.2023.2212782
   Google Scholar
• Thu, Y. M., & Richmond, A. (2010). NF-κB inducing kinase: A key regulator in the immune system and in cancer. Cytokine & Growth Factor Reviews, 21(4), 213–226. https://doi.org/10.1016/j.cytogfr.2010.06.002
   PubMed Web of Science ®Google Scholar
• Tong, X., Liu, X., Tan, X., Li, X., Jiang, J., Xiong, Z., Xu, T., Jiang, H., Qiao, N., & Zheng, M. (2021). Generative Models for De Novo Drug Design. Journal of Medicinal Chemistry, 64(19), 14011–14027. https://doi.org/10.1021/acs.jmedchem.1c00927
   PubMed Web of Science ®Google Scholar
• Valdés-Tresanco, M. S., Valdés-Tresanco, M. E., Valiente, P. A., & Moreno, E. (2021). gmx_MM/PBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS. Journal of Chemical Theory and Computation, 17(10), 6281–6291. https://doi.org/10.1021/acs.jctc.1c00645
   PubMed Web of Science ®Google Scholar
• Vulpetti, A., & Bosotti, R. (2004). Sequence and structural analysis of kinase ATP pocket residues. Farmaco (Societa Chimica Italiana: 1989), 59(10), 759–765. https://doi.org/10.1016/j.farmac.2004.05.010
   PubMedGoogle Scholar
• Wang, H., Gao, Z., Song, P., Hu, B., Wang, J., & Cheng, M. (2019). Molecular dynamics simulation and QM/MM calculation reveal the selectivity mechanism of type I 1/2 kinase inhibitors: The effect of intramolecular H-bonds and conformational restriction for improved selectivity. Physical Chemistry Chemical Physics, 21(43), 24147–24164. https://doi.org/10.1039/c9cp04353e
   PubMed Web of Science ®Google Scholar
• Wang, Z., Sun, H., Yao, X., Li, D., Xu, L., Li, Y., Tian, S., & Hou, T. (2016). Comprehensive evaluation of ten docking programs on a diverse set of protein-ligand complexes: The prediction accuracy of sampling power and scoring power. Physical Chemistry Chemical Physics, 18(18), 12964–12975. https://doi.org/10.1039/c6cp01555g
   PubMed Web of Science ®Google Scholar
• Waterhouse, A., Bertoni, M., Bienert, S., Studer, G., Tauriello, G., Gumienny, R., Heer, F. T., de Beer, T. A. P., Rempfer, C., Bordoli, L., Lepore, R., & Schwede, T. (2018). SWISS-MODEL: Homology modelling of protein structures and complexes. Nucleic Acids Research, 46(W1), W296–W303. https://doi.org/10.1093/nar/gky427
   PubMed Web of Science ®Google Scholar
• Wiederstein, M., & Sippl, M. J. (2007). ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Research, 35(Web Server issue), W407–W410. https://doi.org/10.1093/nar/gkm290
   PubMed Web of Science ®Google Scholar
• Xiao, G., & Sun, S. C. (2000). Negative regulation of the nuclear factor kappa B-inducing kinase by a cis-acting domain. The Journal of Biological Chemistry, 275(28), 21081–21085. https://doi.org/10.1074/jbc.M002552200
   PubMed Web of Science ®Google Scholar
• Xiong, G., Wu, Z., Yi, J., Fu, L., Yang, Z., Hsieh, C., Yin, M., Zeng, X., Wu, C., Lu, A., Chen, X., Hou, T., & Cao, D. (2021). ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Research, 49(W1), W5–W14. https://doi.org/10.1093/nar/gkab255
   PubMed Web of Science ®Google Scholar
• Yap, D. Y. H., & Chan, T. M. (2019). B Cell Abnormalities in Systemic Lupus Erythematosus and Lupus Nephritis-Role in Pathogenesis and Effect of Immunosuppressive Treatments. International Journal of Molecular Sciences, 20(24), 6231. https://doi.org/10.3390/ijms20246231
   PubMed Web of Science ®Google Scholar
• Yu, C., Li, P., Dang, X., Zhang, X., Mao, Y., & Chen, X. (2022). Lupus nephritis: New progress in diagnosis and treatment. Journal of Autoimmunity, 132, 102871. https://doi.org/10.1016/j.jaut.2022.102871
   PubMed Web of Science ®Google Scholar
• Yuan, Y., Zhang, H., Li, D., Li, Y., Lin, F., Wang, Y., Song, H., Liu, X., Li, F., & Zhang, J. (2022). PAK4 in cancer development: Emerging player and therapeutic opportunities. Cancer Letters, 545, 215813. https://doi.org/10.1016/j.canlet.2022.215813
   PubMed Web of Science ®Google Scholar
• Zhang, N., & Zhao, H. (2016). Enriching screening libraries with bioactive fragment space. Bioorganic & Medicinal Chemistry Letters, 26(15), 3594–3597. https://doi.org/10.1016/j.bmcl.2016.06.013
   PubMed Web of Science ®Google Scholar