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Binding patterns of derivatives of fisetin and chrysin to the enzyme complex cyclin-dependent kinase 6/cyclin D

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Abstract

Clinical inhibitors of cell-cycle regulatory enzyme cyclin-dependent kinase 6 (CDK6) are not free of harmful consequences to human bodies. Flavonoids fisetin and chrysin bestow anti-cancer benefits by inhibiting the activities of CDK6 with strong binding affinities. To understand the structure requirement of such inhibitory behaviour, docking and molecular dynamics (MD) simulations were performed on chosen three derivatives each of fisetin and chrysin along with the parent flavonoids. Docking studies revealed more negative binding energies of the derivatives than the parent molecules. MD simulations suggested appreciable stability of the derivatives in the systems. CDK6 association with ring A OH was minute in fisetin, replacing the same with one α-naphtha group in fisetin_3 resulting in enhanced long-range interactions. Interaction of ring A OH groups was significant in chrysin. The additional fluorine atom along with ring C OH and OCH3substituents in chrysin_2 induced a greater number of favourable interactions with CDK6.

The selected ligands were docked into the ATP competitive binding site of rigid receptor CDK6/cyclin D using AutoDock 4.2. Stable conformations of the ligands were searched using Lamarckian Genetic Algorithm. Lowest energy poses of the best docked derivatives that resembled experimental conformation of co-crystallised ligand fisetin (fisetin_3, chrysin_3 and chrysin_2), along with fisetin and chrysin which were subjected to MD simulations. Ligand protein interactions in an aqueous environment were modelled using CHARMM27 force field accommodated in GROMACS 2022. MM-PBSA binding free energies of the ligands to CDK6 were computed using g_mmpbsa module of GROMACS.

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Data availability

GAUSSIAN09 is a commercial software and information on it can be obtained through https://gaussian.com/. GROMACS 5.2.1 is a free software available at https://manual.gromacs.org/documentation/5.1.2/index.html. Python scripts, parameter files and required packages for MM-PBSA calculations in GROMACS can be obtained from https://rashmikumari.github.io/g_mmpbsa/. AutoDock version 4.2 is publicly obtainable through https://autodock.scripps.edu/download-autodock4/. BIOVIA Discovery Studio Visualizer can be obtained for academic purposes freely through https://discover.3ds.com/discovery-studio-visualizer-download. All required data are depicted through figures, shown in tables or incorporated in the supporting information. Input and parameter files that are required to reproduce the data and relevant output files can be obtained from the corresponding on request.

References

  1. Ortega S, Malumbres M, Barbacid M (2002) Cyclin D-dependent Kinases, INK4 inhibitors and Cancer. Biochim Biophys Acta Rev Cancer 1602(1):73–87. https://doi.org/10.1016/s0304-419x(02)00037-9

    Article  CAS  Google Scholar 

  2. Rader JA, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S, Parasuraman S, Caponigro G, Schnepp RW, Wood AC, Pawel B, Cole KA, Maris JM (2013) Dual CDK4/CDK6 Inhibition Induces Cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res 19:6173–6182

    Article  CAS  PubMed  Google Scholar 

  3. Wu J, Qian J, Li C, Kwok L, Cheng F, Liu P, Catalina P, Kotton D, Vaziri C, Anderlind C, Spira A, Cardoso WV, Lü J (2010) miR-129 regulates cell proliferation by downregulating Cdk6 expression. Cell Cycle 9(9):1809–1818. https://doi.org/10.4161/cc.9.9.11535

    Article  CAS  PubMed  Google Scholar 

  4. Wang G, Zheng L, Yu Z, Liao G, Lu L, Xu R, Zhao Z, Chen G (2012) Increased Cyclin-dependent kinase 6 expression in bladder cancer. Oncol Lett 4(1):43–46. https://doi.org/10.3892/ol.2012.695

    Article  PubMed  PubMed Central  Google Scholar 

  5. Murphy CG, Dickler M (2015) The role of CDK4/6 Inhibition in breast cancer. Oncologist 20(6):1–8. https://doi.org/10.1007/s11864-019-0651-4

    Article  Google Scholar 

  6. Xia B, Yang S, Leu T, Lou G (2015) miR-211 suppresses epithelial ovarian cancer proliferation and cell- cycle progression by targeting Cyclin D1 and CDK6. Mol Cancer 14:1–13. https://doi.org/10.1186/s12943-015-0322-4

    Article  CAS  Google Scholar 

  7. Colamaio M, Borbone E, Russo L, Bianco M, Federico A, Califano D, Chiappetta G, Pallante P, Troncone G, Sabrina B, Fusco A (2011) miR-191 down-regulation plays a role in thyroid follicular tumours through CDK6 targeting. J Clin Endocrinol Metab 96(12):915–924. https://doi.org/10.1210/jc.2011-0408

    Article  CAS  Google Scholar 

  8. Sherr CJ, Beach D, Shapiro GI (2016) Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov 6(4):353–367. https://doi.org/10.1158/2159-8290.cd-15-0894

    Article  CAS  PubMed  Google Scholar 

  9. Peyressatre M, Prével C, Pellerano M, Morris MC (2015) Targeting cyclin-dependent kinases in human cancers: from small molecules to peptide inhibitors. Cancers 7(1):179–237. https://doi.org/10.3390/cancers7010179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fotsis T, Pepper MS, Aktas E, Breit S, Rasku S, Adlercreutz H, Wӓhӓlӓ K, Montesano R, Schweigerer L (1997) Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res 57(14):2916–2921

    CAS  PubMed  Google Scholar 

  11. Pieta PG (2000) Flavonoids as antioxidants. J Nat Prod 63:1035–1042

    Article  Google Scholar 

  12. Kim HP, Son KH, Chang HW, Kang SS (2004) Anti-inflammatory plant flavonoids and cellular action mechanisms. J Pharmacol Sci 96(3):229–245. https://doi.org/10.1254/jphs.crj04003x

    Article  CAS  PubMed  Google Scholar 

  13. Salmela AL, Pouwels J, Varis A, Kukkonen AM, Toivonen P, Halonen PK, Perala M, Kallioniemi O, Gorbsky GJ, Kallio MJ (2009) Dietary flavonoid fisetin induces forced exit from mitosis by targeting the mitotic spindle checkpoint. Carcinogenesis 30:1032–1040. https://doi.org/10.1093/carcin/bgp101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pal HC, Diamon AC, Strickland LR, Kappes JC, Katiyar SK, Elmets CA, Athar M, Afaq F (2015) Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma. Oncotarget 7:1227–1241. https://doi.org/10.18632/oncotarget.6237

    Article  PubMed Central  Google Scholar 

  15. Mukhtar E, Adhami VM, Siddiqui M, Verma AJ, Mukhtar H (2016) Fisetin enhances chemotherapeutic effect of cabazitaxel against human prostate cancer cells. Mol Cancer 15(12):2863–2874. https://doi.org/10.1158/1535-7163.mct-16-0515

    Article  CAS  Google Scholar 

  16. Li R, Zhao Y, Chen J, Shao S, Zhang X (2014) Fisetin inhibits migration, invasion and epithelial-mesenchymal transition of LMP1-positive nasopharyngeal carcinoma cells. Mol Med Rep 9(2):413–418. https://doi.org/10.3892/mmr.2013.1836

    Article  CAS  PubMed  Google Scholar 

  17. Khan MI, Adhami VM, Lall RK, Sechi M, Joshi DC, Haider OM, Syed DN, Siddiqui IA, Chiu S, Mukhtar H (2014) YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by small molecule fisetin. Oncotarget 5(9):2462–2474. https://doi.org/10.18632/oncotarget.1790

    Article  PubMed  PubMed Central  Google Scholar 

  18. Syed DN, Adhami VM, Khan N, Khan MI, Mukhtar H (2016) Exploring the molecular targets of dietary Flavonoids fisetin in cancer. Semin Cancer Biol 40–41:130–140. https://doi.org/10.1016/j.semcancer.2016.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li J, Qu W, Cheng Y, Sun Y, Jiang Y, Zou T, Wang Z, Xu Y, Zhao H (2014) The inhibitory effect of intravesical fisetin against bladder cancer by induction of p53 and down-regulation of NF-kappa B pathways in a rat bladder carcinogenesis model. Basic Clin Pharmacol Toxicol 115(4):321–329. https://doi.org/10.1111/bcpt.12229

    Article  CAS  PubMed  Google Scholar 

  20. Kang KA, Piao MJ, Hyun JW (2014) Fisetin induces apoptosis in human nonsmall lung cancer cells via a mitochondria-mediated pathway. In Vitro Cell Dev Biol Anim 51(3):300–309. https://doi.org/10.1007/s11626-014-9830-6

    Article  CAS  PubMed  Google Scholar 

  21. Jang KY, Jeong SJ, Kim SH, Jung JH, Kim JH, Kim SH (2012) Activation of reactive oxygen species/AMP activated protein kinase signalling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. Cancer Letter 319(2):197–202. https://doi.org/10.1016/j.canlet.2012.01.008

    Article  CAS  Google Scholar 

  22. Lu X, Jung JI, Cho HJ, Lim DY, Lee HS, Chun HS, Kwon DY, Park HJY (2005) Fisetin Inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. J Nutr 135(12):2884–2890. https://doi.org/10.1093/jn/135.12.2884

    Article  CAS  PubMed  Google Scholar 

  23. Khan N, Afaq F, Khusro FH, Mustafa AV, Suh Y, Mkhtar H (2012) Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signalling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer 130(7):1695–1705. https://doi.org/10.1002/ijc.26178

    Article  CAS  PubMed  Google Scholar 

  24. Syed DN, Agaq F, Maddodi N, Johnson JJ, Sarfaraz S, Ahmad A, Setaluri V, Mukhtar H (2011) Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/β-catenin signalling and decreased mitf levels. J Investig Dermatol 131(6):1291–1299. https://doi.org/10.1038/jid.2011.6

    Article  CAS  PubMed  Google Scholar 

  25. Syed DN, Chamcheu JC, Khan MI, Sechi M, Lall RK, Adhami VM, Mukhtar H (2014) Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modelling. Biochem Pharmacol 89(3):349–360. https://doi.org/10.1016/j.bcp.2014.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kasala ER, Bodduluru LN, Madana RM, Athira KV, Gogoi R, Barua CC (2016) Chemopreventive and therapeutic potential of Chrysin in cancer: mechanistic perspectives. Toxicol Lett 233(2):214–225. https://doi.org/10.1016/j.toxlet.2015.01.008

    Article  CAS  Google Scholar 

  27. Monasterio A, Urdaci MC, Pinchuk IV, Lopez-Moratalla N, Martinez-Irujo JJ (2004) Flavonoids induce apoptois in human leukemia U937 cells through caspase-and caspase-calpain-dependent pathways. Nutr Cancer 50(1):90–100. https://doi.org/10.1207/s15327914nc5001_12

    Article  CAS  PubMed  Google Scholar 

  28. Li H, Huang Q, Ong CN, Yang XF, Shen HM (2010) Chrysin sensitizes tumour necrosis factor-alpha-induced apoptosis in human tumour cells via suppression of nuclear factor-kappaB. Cancer Lett 293(1):109–116. https://doi.org/10.1016/j.canlet.2010.01.002

    Article  CAS  PubMed  Google Scholar 

  29. Khan M, Halagowder D, Devaraj NS (2011) Methylated chrysin induces co-ordinated attenuation of the canonical Wnt and NF-kB signalling pathway and upregulates apoptotic gene expression in the early hepatocarcinogenesis rat model. Chem BiolIntercat 193(1):12–21. https://doi.org/10.1016/j.cbi.2011.04.007

    Article  CAS  Google Scholar 

  30. Kachadourian R, Day BJ (2006) Flavonoid-induced glutathione depletion: potential implications for cancer treatment. Free Radic Biol Med 41(1):65–76. https://doi.org/10.1016/j.freeradbiomed.2006.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schindler R, Mentlein R (2006) Flavonoids and vitamin E reduce the release of the angiogenic peptide vascular endothelial growth factor from human tumor cells. J Nutr 136(6):1477–1482. https://doi.org/10.1093/jn/136.6.1477

    Article  CAS  PubMed  Google Scholar 

  32. Gao AM, Ke ZP, Shi F, Sun GC, Chen H (2013) Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway. Chem Biol Interact 206(1):100–108. https://doi.org/10.1016/j.cbi.2013.08.008

    Article  CAS  PubMed  Google Scholar 

  33. Yang B, Huang J, Xiang T, Yin X, Luo X, Huang J, Luo F, Li H, Ren G (2014) Chrysin inhibits metastatic potential of human triple-negative breast cancer cells by modulating matrix metalloproteinase-10, epithelial to mesenchymal transition, and PI3K/Akt signalling pathway. J ApplToxicol 34(1):105–112. https://doi.org/10.1002/jat.2941

    Article  CAS  Google Scholar 

  34. Chen SS, Corteling R, Stevanato L, Sinden J (2012) Polyphenols inhibit indoleamine 3.5-dioxygenase-1 enzymatic activity-a role of immunomodulation in chemoprevention. Discov Med 14(78):327–333

    PubMed  Google Scholar 

  35. Zhang Q, Zhao XH, Wang ZH (2009) Cytotoxicity of flavones and flavanols to a human oesophageal squamous cell carcinoma cell line (KYSE-510) by induction of G2/M arrest and apoptosis. Toxicolin Vitro 23(5):797–807. https://doi.org/10.1016/j.tiv.2009.04.007

    Article  CAS  Google Scholar 

  36. Weng MS, Ho YS, Lin JK (2005) Chrysin induces G1 phase cell cycle arrest in C6 glioma cells through inducing p21Waf1/Cip1 expression: involvement of p38 mitogen-activated protein kinase. Biochem Pharmacol 69(12):1815–1827. https://doi.org/10.1016/j.bcp.2005.03.011

    Article  CAS  PubMed  Google Scholar 

  37. O’Dwyer PJ, LoRusso P, DeMichele A, Gupta V, Barbi A, Dials I, Chen H, Courtney R, Wilner K, Schwartz GK (2007) A Phase I dose escalation trial of a daily oral CDK 4/6 inhibitor PD-0332991. J Clin Oncol 25:3550

    Article  Google Scholar 

  38. Infante JR, Cassier PA, Gerecitano JF, Witteveen PO, Chugh R, Ribrag V, Chakraborty A, Matano A, Dobson JR, Crystal AS, Parasuraman S, Shapiro GI (2016) A phase I study of the cyclin dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas. Clin Cancer Res 22(23):5696–5705. https://doi.org/10.1158/1078-0432.ccr-16-1248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shapiro G, Rosen LS, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, Tolaney MB, Rasco DW, Kulanthaivel P, Li Q, Hu T, Cronier D, Chan EM, Flaherty K, Wen PY, Patnaik A (2013) A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer. J Clin Oncol 31(15):2500. https://doi.org/10.1200/jco.2013.31.15_suppl.2500

    Article  Google Scholar 

  40. Phelps MA, Lin TS, Johnson AJ, Hurh E, Rozewski DM, FarleyKL WuD, Blum KA, Fischer B, Mitchell SM, Moran ME, Moran ME, Brooker-McEldowney M, Heerema NA, Jarjoura D, Schaaf LJ, Byrd JC, Grever MR, Dalton JT (2009) Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood 113(12):2637–2645. https://doi.org/10.1182/blood-2008-07-168583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chohan TA, Qayyum A, Rehman K, Tariq M, Akash MSH (2018) An insight into the emerging role of Cyclin-dependent kinase inhibitors as potential therapeutic agents for the treatment of advanced cancers. Biomed Pharmacother 107:1326–1341. https://doi.org/10.1016/j.biopha.2018.08.116

    Article  CAS  PubMed  Google Scholar 

  42. Youns M, Hegazy WAH (2017) The natural flavonoid fisetin inhibits cellular proliferation of hepatic, colorectal, and pancreatic cancer cells through modulation of multiple signaling pathways. PLoS ONE 12(1):1–18. https://doi.org/10.1371/journal.pone.0169335

    Article  CAS  Google Scholar 

  43. Li J, Cheng Y, Qu W, Sun Y, Wang Z, Wang H, Tian B (2010) Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-Kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol 108(2):84–93. https://doi.org/10.1111/j.1742-7843.2010.00613.x

    Article  CAS  PubMed  Google Scholar 

  44. Haddad AQ, Venkateswaran V, Viswanathan L, Teahan SJ, Fleshner NE, Klotz LH (2006) Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis 9(1):68–76. https://doi.org/10.1038/sj.pcan.4500845

    Article  CAS  PubMed  Google Scholar 

  45. Khan N, Afaq F, Syed DN, Mukhtar H (2008) Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. Carcinogenesis 29(5):1049–1056. https://doi.org/10.1093/carcin/bgn078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rasouli S, Zarghami N (2018) Synergistic growth inhibitory effects of chrysin and metformin combination on breast cancer cells through hTERT and Cyclin D1 suppression. Asian Pac J Cancer Prev 19(4):977–982. https://doi.org/10.22034/apjcp.2018.19.4.977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lu H, Chang DJ, Baratte B, Meijer L, Schulze-Gahmen U (2005) Crystal structure of a human cyclin-dependent kinase 6 complex with a Flavonol inhibitor. Fisetin J Med Chem 48(3):737–743. https://doi.org/10.1021/jm049353p

    Article  CAS  PubMed  Google Scholar 

  48. Khuntawee W, Rungrotmongkol T, Hunnongbua S (2012) Molecular dynamic behavior and binding affinity of flavonoid analogues to the cyclin dependent kinase 6/cyclin D complex. J Chem Inf Model 52(1):76–83. https://doi.org/10.1021/ci200304v

    Article  CAS  PubMed  Google Scholar 

  49. Zhang J, Zhang L, Xu Y, Jiang S, Shao Y (2018) Deciphering the binding behaviour of flavonoids to the cyclin dependent kinase 6/cyclin D complex. PLoS ONE 13(5):0196651

    Google Scholar 

  50. Chiruta C, Schubert D, Dargusch R, Maher P (2012) Chemical modification of the multitarget neuroprotective compound Fisetin. JMed Chem 55(1):378–389. https://doi.org/10.1021/jm2012563

    Article  CAS  Google Scholar 

  51. Fujimoto AJ, Nema D, Ninomiya M, Koketsu M, Sadanari H, Takemoto M, Daikoku T, Maruyama T (2018) An in silico-designed flavone derivative, 6-fluoro-4’-hydroxy-3’, 5’-dimetoxyflavone, has a greater anti-Human cytomegalovirus effect than ganciclovir in infected cells. Antivir Res 154:10–16. https://doi.org/10.1016/j.antiviral.2018.03.006

    Article  CAS  PubMed  Google Scholar 

  52. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich A, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, HendersonT RD, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ (2009) Gaussian 09, revision D.01. Gaussian Inc, Wallingford

    Google Scholar 

  53. Rose PW, Beran B, Bi C, Bluhm WF, Dimitropoulos D, Goodsell DS, Prlic A, Quesada M, Quinn GB, Westbrook JD, Young J, Yukich B, Zardecki C, Berman HM, Bourne PE (2010) The RCSB protein data bank: redesigned web site and web services. Nucleic Acids Res 39:392–401. https://doi.org/10.1093/nar/gkq1021

    Article  CAS  Google Scholar 

  54. Morris GM, Huey R, Lindstorm W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791. https://doi.org/10.1002/jcc.21256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cosconati S, Forli S, Perryman AL, Harris R, Goodsell DS, Olson AJ (2010) Virtual screening with AutoDock: theory and practice. Expert Opin Drug Discov 5(6):597–607. https://doi.org/10.1517/17460441.2010.484460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E (2015) GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1–2:19–25. https://doi.org/10.1016/j.softx.2015.06.001

    Article  Google Scholar 

  57. Bjelkmar P, Larsson P, Cuendet MA, Hess B, Lindahl E (2009) Implementation of the CHARMM Force Field in GROMACS: Analysis of protein stability effects from correction maps, virtual interaction sites, and water models. J Chem Theory Comput 6(2):459–466. https://doi.org/10.1021/ct900549r

    Article  CAS  Google Scholar 

  58. MacKerell AD, Bashford D, Bellot M, Dunbrack RL, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiόrkiewicz-Kuczera J, Yin D, Karplus M (1998) All-Atom empirical potential for molecular modelling and dynamics studies of proteins. J Phys Chem B 102(18):3586–3616. https://doi.org/10.1021/jp973084f

    Article  CAS  PubMed  Google Scholar 

  59. Kumari R, Kumar R, Lynn A, Open Source Drug Discovery Consortium (2014) g_mmpbsa A GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 54(7):1951–1962

    Article  CAS  PubMed  Google Scholar 

  60. Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case DA, Cheatham TE (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889–897. https://doi.org/10.1021/ar000033j

    Article  CAS  PubMed  Google Scholar 

  61. Platania CBM, Paola LD, Leggio GM, Romano GL, Drago F, Salomone S, Bucolo C (2015) Molecular features of interaction between VEGFA and anti-angiogenic drugs used in retinal diseases: a computational approach. Front Pharmacol 6:248

    Article  PubMed  PubMed Central  Google Scholar 

  62. Nicholls A, Sharp KA, Honig B (1991) Protein folding and association-insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins 11:281–296. https://doi.org/10.1002/prot.340110407

    Article  CAS  PubMed  Google Scholar 

  63. Morgan D (1995) Principles of CDK regulation. Nature 374:131–134. https://doi.org/10.1038/374131a0

    Article  CAS  PubMed  Google Scholar 

  64. Tadesse S, Yu M, Kumarasiri M, Le BT, Wang S (2015) Targeting CDK6 in cancer: State of the art and new insights. Cell Cycle 14:3220–3230. https://doi.org/10.1080/15384101.2015.1084445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. BIOVIA, Dassault Systèmes (2019) [BIOVIA Discovery Studio Visualizer], [version 20.1.0.19295]. San Diego: Dassault Systèmes. http://www.accelrys.com

  66. Turner P (2005) XMGRACE (version 5.1.25) [computer software].Center for Coastal and Land-Margin research, Oregon Graduate Institute of Science and Technology, Bearverton.

  67. Yousuf M, Khan P, Shamsi A, Shahbaaz M, Hasan GM, Haque QMR, Christoffels A, Islam A, Hassan MI (2020) Inhibiting CDK6 activity by quercetin is an attractive strategy for cancer therapy. ACS Omega 5(42):27480–27491. https://doi.org/10.1021/acsomega.0c03975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the Department of Chemical Sciences, Tezpur University, for the computational facilities required for this work. The authors also thank the institutional supercomputing facility Paramshavak in which MD simulations were carried out.

Funding

This research was supported by Council of Scientific & Industrial Research (CSIR): 01(3080)/21 and by Department of Science and Technology: CRG/2023/002847, Government of India. S.S. received funding for carrying out the research work from Department of Science and Technology, Government of India, through Innovation in Science Pursuit for Inspired Research (INSPIRE) program-IF190945.

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  1. CMML–Catalysis and Molecular Modelling Lab, Department of Chemical Sciences, Tezpur University, Napaam, Tezpur, Assam, 784028, India

    Srutishree Sarma, Nand Kishor Gour, Dikshita Dowerah, Saheen Shehnaz Begum & Ramesh Chandra Deka

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Contributions

S.S. carried out docking and MD simulations studies. R.C.D, N.K.G and S.S.B framed the outline of this work and helped in writing the manuscript. D.D helped during the revision of the manuscript. All the authors reviewed and equally contributed to this manuscript.

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Correspondence to Ramesh Chandra Deka.

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Sarma, S., Gour, N.K., Dowerah, D. et al. Binding patterns of derivatives of fisetin and chrysin to the enzyme complex cyclin-dependent kinase 6/cyclin D. Theor Chem Acc 142, 116 (2023). https://doi.org/10.1007/s00214-023-03043-3

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