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2000
Volume 22, Issue 1
  • ISSN: 1570-1786
  • E-ISSN: 1875-6255

Abstract

Cancer is a global health issue, and cancer cells' resistance to existing treatments has prompted a search for new anticancer drugs. The DNA of cancer cells is regarded as the primary target for developing new molecules. studies aid in the optimization of current pharmacophores and the development of new molecules. This study aimed to optimize the pharmacophore utilizing QSAR studies and pharmacophore mapping to generate novel chemical entities (NCEs) of pyrimidine derivatives as DNA inhibitors for cancer treatment. Furthermore, these NCEs were subjected to molecular docking and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) screening to determine their drug-likeness. This study used Schrodinger's Maestro (13.4) software for pharmacophore mapping, QSAR, molecular docking, and ADME. Toxicity was determined using the Pro Tox II online tool. Pharmacophore mapping was performed using the phase module. The QSAR model was generated using an atom-based QSAR approach. The Qik prop module was utilized for ADME prediction. Molecular docking was done in Standard precision mode. In pharmacophore mapping, we discovered that the DHHRR_1 hypothesis fitted best, with a survival score of 5.4408. The optimal atom-based QSAR model produced correlation coefficients of R2 = 0.9487 and Q2 = 0.8361. Based on QSAR research, a new set of 43 derivatives was generated. These compounds pass all ADMET requirements. In molecular docking investigations, three compounds demonstrated binding with key amino acids with a significant dock score comparable to the standard. Considering docking data and pharmacokinetic behavior of newly developed compounds, molecules NC10, NC9, and NC43 have the highest DNA binding capability.

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References

  1. PatilS.M. BhandariS.V. Lett. Drug Des. Discov.202320677979110.2174/1570180819666220414102310
     [Google Scholar]
  2. RenaudB. BudaM. LewisB.D. PujolJ.F. Biochem. Pharmacol.197524181739174210.1016/0006‑2952(75)90018‑017
     [Google Scholar]
  3. SungH. FerlayJ. SiegelR.L. LaversanneM. SoerjomataramI. JemalA. BrayF. CA Cancer J. Clin.202171320924910.3322/caac.2166033538338
     [Google Scholar]
  4. WHO.Available From: https://www.who.int/health-topics/cancer#tab=tab_1 2023
  5. Mayo Clinic.Available From: https://www.mayoclinic.org/tests-procedures/chemotherapy/about/pac-20385033#:~:text=Chemotherapy%20can%20be%20used%20to,some%20of%20the%20cancer%20cells 2024
  6. MunirA. AzamS. MehmoodA. Drug Des.20165310.4172/2169‑0138.1000137
     [Google Scholar]
  7. GavandeN.S. VanderVere-CarozzaP.S. HinshawH.D. JalalS.I. SearsC.R. PawelczakK.S. TurchiJ.J. Pharmacol. Ther.2016160658310.1016/j.pharmthera.2016.02.00326896565
     [Google Scholar]
  8. Cleveland Clinic.Available From: https://my.clevelandclinic.org/health/treatments/24323-chemotherapy-drugs 2023
  9. QuY. QinS. YangZ. LiZ. LiangQ. LongT. WangW. ZengD. ZhaoQ. DaiZ. NiQ. ZhaoF. KimW. Hou.J. Biomed. Pharmacother.202316911587710.1016/j.biopha.2023.11587737951025
     [Google Scholar]
  10. LaneA.N. FanT.W.M. Nucleic Acids Res.20154342466248510.1093/nar/gkv04725628363
     [Google Scholar]
  11. DeanJ.L. McClendonA.K. KnudsenE.S. J. Biol. Chem.201228734290752908710.1074/jbc.M112.36549422733811
     [Google Scholar]
  12. HessJ.A. KhasawnehM.K. BBA Clin.2015315216110.1016/j.bbacli.2015.01.00626674389
     [Google Scholar]
  13. PerryM. GhosalG. Front. Mol. Biosci.2022991669710.3389/fmolb.2022.91669735782873
     [Google Scholar]
  14. PolesieS. GillstedtM. SchmidtS.A.J. EgebergA. PottegårdA. KristensenK. Br. J. Cancer202312871311131910.1038/s41416‑023‑02172‑736739322
     [Google Scholar]
  15. BanerjeeP. DehnbostelF.O. PreissnerR. Front Chem.2018636210.3389/fchem.2018.0036230271769
     [Google Scholar]
  16. OlivieriA. ManzioneL. Ann. Oncol.200718Suppl. 6vi42vi4610.1093/annonc/mdm22317591830
     [Google Scholar]
  17. GomaaM. GadW. HusseinD. PottooF.H. TawfeeqN. AlturkiM. AlfahadD. AlanaziR. SalamaI. AzizM. ZahraA. HanafyA. Pharmaceuticals (Basel)202417218910.3390/ph1702018938399404
     [Google Scholar]
  18. TahtaouiC. DemaillyA. GuidemannC. JoyeuxC. SchneiderP. J. Org. Chem.201075113781378510.1021/jo100566c20446707
     [Google Scholar]
  19. TiwariA.K. SodaniK. DaiC. AbuznaitA.H. SinghS. XiaoZ.J. PatelA. TaleleT.T. FuL. KaddoumiA. GalloJ.M. ChenZ.S. Cancer Lett.2013328230731710.1016/j.canlet.2012.10.00123063650
     [Google Scholar]
  20. OyewoleR.O. OyebamijiA.K. SemireB. Heliyon202065e0392610.1016/j.heliyon.2020.e0392632462084
     [Google Scholar]
  21. VasilyevaS.V. ShtilA.A. PetrovaA.S. BalakhninS.M. AchigechevaP.Y. StetsenkoD.A. SilnikovV.N. Bioorg. Med. Chem.20172551696170210.1016/j.bmc.2017.01.03828169081
     [Google Scholar]
  22. Al-GhobashyM.A. KamalS.M. El-SayedG.M. AttiaA.K. NagyM. ElZeinyA. ElrakaibyM.T. NoohM.M. AbbassiM. AzizR.K. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.2018109248949810.1016/j.jchromb.2018.06.04330008305
     [Google Scholar]
  23. BenderL. PflumioC. TrenszP. PierardL. KalishM. FischbachC. PetitT. Cancer Treat. Res. Commun.20233610073810.1016/j.ctarc.2023.10073837390791
     [Google Scholar]
  24. Abo-SalemH.M. AboBakr AliE. El-MowafiS.A. Abdel-AzizM.S. El-SawyE.R. Abd El SalamH.A. J. Mol. Struct.2024129613686010.1016/j.molstruc.2023.136860
     [Google Scholar]
  25. LapidotA. BaranN. ManorH. Nucleic Acids Res.198917388390010.1093/nar/17.3.8832922274
     [Google Scholar]
  26. MahapatraA. PrasadT. SharmaT. Fut. J. Pharmaceut. Sci.20217112310.1186/s43094‑021‑00274‑8
     [Google Scholar]
  27. KolasaniB.P. J Clin Diagn Res.20161011FC17FC2010.7860/JCDR/2016/22384.8918
     [Google Scholar]
  28. BakshiA. IturraF.E. AlambanA. Rosas-SalvansM. DumontS. AydoganM.G. Cell.20231862146944709
     [Google Scholar]
  29. AlbrattyM. AlhazmiH. A. Arabian J Chem.202315103846104709
     [Google Scholar]
  30. EdelmanL.B. EddyJ.A. PriceN.D. Wiley Interdiscip. Rev. Syst. Biol. Med.20102443845910.1002/wsbm.7520836040
     [Google Scholar]
  31. ChenC.Y.C. J. Taiwan Inst. Chem. Eng.200940215516110.1016/j.jtice.2008.07.010
     [Google Scholar]
  32. GarridoA. LepailleurA. MignaniS.M. DallemagneP. RochaisC. Eur. J. Med. Chem.202019511229010.1016/j.ejmech.2020.11229032283295
     [Google Scholar]
  33. SharmaV. WakodeS. KumarH. Chemoinformatics and Bioinformatics in the Pharmaceutical Sciences.AmsterdamElsevier2021275310.1016/B978‑0‑12‑821748‑1.00004‑X
     [Google Scholar]
  34. JawarkarR.D. KhanA.N. BhagatD.R. KhataleP.N. BurakaleP.V. FarooquiS. MaliS.N. Chem. Phys. Imp.2024810047910.1016/j.chphi.2024.100479
     [Google Scholar]
  35. HarderE. DammW. MapleJ. WuC. ReboulM. XiangJ.Y. WangL. LupyanD. DahlgrenM.K. KnightJ.L. KausJ.W. CeruttiD.S. KrilovG. JorgensenW.L. AbelR. FriesnerR.A. J. Chem. Theory Comput.201612128129610.1021/acs.jctc.5b0086426584231
     [Google Scholar]
  36. ShivakumarD. J. Chem. Theory Comput.2010651509151910.1021/ct900587b
     [Google Scholar]
  37. JorgensenW.L. MaxwellD.S. Tirado-RivesJ. J. Am. Chem. Soc.199611845112251123610.1021/ja9621760
     [Google Scholar]
  38. JorgensenW.L. Tirado-RivesJ. J. Am. Chem. Soc.198811061657166610.1021/ja00214a00127557051
     [Google Scholar]
  39. Schrodinger.Available From: https://www.schrodinger.com/products/qikprop 2016
  40. MarondedzeE.F. GovenderK.K. GovenderP.P. J. Mol. Graph. Model.202010110771110.1016/j.jmgm.2020.10771132898834
     [Google Scholar]
  41. ChoubeyS.K. JeyaramanJ. J. Mol. Graph. Model.201670546910.1016/j.jmgm.2016.09.00827668885
     [Google Scholar]
  42. PedrettiA. De LucaL. MarconiC. RegazzoniL. AldiniG. VistoliG. Bioorg. Med. Chem.201119154544455110.1016/j.bmc.2011.06.02721741846
     [Google Scholar]
  43. SharmaV. SharmaV. KumarP. KumarV. Pak. J. Pharm. Sci.20142761851185525362609
     [Google Scholar]
  44. SinghM. RajawatJ. KuldeepJ. ShuklaN. MishraD.P. SiddiqiM.I. J. Biomol. Struct. Dyn.202240188494850710.1080/07391102.2021.191322933950778
     [Google Scholar]
  45. VermaG. KhanM.F. AkhtarW. AlamM.M. AkhterM. AlamO. HasanS.M. ShaquiquzzamanM. Arab. J. Chem.20191284815483910.1016/j.arabjc.2016.09.019
     [Google Scholar]
  46. ReddyK.K. SinghS.K. DessalewN. TripathiS.K. SelvarajC. J. Enzyme Inhib. Med. Chem.201227333934710.3109/14756366.2011.59080321699459
     [Google Scholar]
  47. GaoW. MaX. YangH. LuanY. AiH. J. Mol. Graph. Model.202211610823910.1016/j.jmgm.2022.10823935696774
     [Google Scholar]
  48. DixonS.L. SmondyrevA.M. RaoS.N. Chem. Biol. Drug Des.200667537037210.1111/j.1747‑0285.2006.00384.x16784462
     [Google Scholar]
  49. SoukainaE. Al-ZaqriN. WaradI. IchouH. YassineK. GuenounF. BouachrineM. J. Mol. Struct.2023128213521910.1016/j.molstruc.2023.135219
     [Google Scholar]
  50. MirzaeiS. GhodsiR. HadizadehF. SahebkarA. BioMed Res. Int.2021202112010.1155/2021/648080434485522
     [Google Scholar]
  51. Schrodinger.Available From: https://newsite.schrodinger.com/life-science/learn/white-papers/docking-and-scoring/ 2016
  52. Alexis Respect KouassiK. GaniyouA. BeniéA. Guy-Richard KonéM. kouakou NobelN.G. Valery BohoussouK. Karime CoulibalyW. Am. J. Pharmacol. Sci.20219112910.12691/ajps‑9‑1‑1
     [Google Scholar]
  53. MaiorovV.N. CrippenG.M. J. Mol. Biol.1994235262563410.1006/jmbi.1994.10178289285
     [Google Scholar]
  54. AZO Life Science.Available From: https://www.azolifesciences.com/article/What-is-Lipinskis-Rule-of-5.aspx 2024
  55. LipinskiC.A. LombardoF. DominyB.W. FeeneyP.J. Adv. Drug Deliv. Rev.2001461-332610.1016/S0169‑409X(00)00129‑011259830
     [Google Scholar]
  56. SahaB. DasA. JangidK. KumarA. KumarV. JaitakV. Curr. Res. Struct. Biol.2024710012410.1016/j.crstbi.2024.10012438292820
     [Google Scholar]
  57. BanerjeeP. EckertA.O. SchreyA.K. PreissnerR. Nucleic Acids Res.201846W1W257W26310.1093/nar/gky31829718510
     [Google Scholar]
  58. LankaG. BegumD. BanerjeeS. AdhikariN. PY. GhoshB. Comput. Biol. Med.202316610748110.1016/j.compbiomed.2023.10748137741229
     [Google Scholar]
  59. SchreinerW. KarchR. KnappB. IlievaN. Comput. Math. Methods Med.201220121910.1155/2012/17352123019425
     [Google Scholar]
  60. FangL. GouS. ZhaoJ. SunY. ChengL. Eur. J. Med. Chem.20136984284710.1016/j.ejmech.2013.07.00424121235
     [Google Scholar]
  61. PatelV.K. SinghA. JainD.K. PatelP. VeerasamyR. SharmaP.C. RajakH. Fut. J. Pharmaceut. Sci.201732717810.1016/j.fjps.2017.03.003
     [Google Scholar]
  62. MatovićZ.D. MrkalićE. BogdanovićG. KojićV. MeetsmaA. JelićR. J. Inorg. Biochem.201312113414410.1016/j.jinorgbio.2013.01.00623376555
     [Google Scholar]
  63. GhanbariH. GhanbariR. DelazarA. EbrahimiS.N. MemarM.Y. MoghadamS.B. HamedeyazdanS. NazemiyehH. Toxicon202323410729110.1016/j.toxicon.2023.10729137734456
     [Google Scholar]
  64. FriesnerR.A. MurphyR.B. RepaskyM.P. FryeL.L. GreenwoodJ.R. HalgrenT.A. SanschagrinP.C. MainzD.T. J. Med. Chem.200649216177619610.1021/jm051256o17034125
     [Google Scholar]
  65. HalgrenT.A. MurphyR.B. FriesnerR.A. BeardH.S. FryeL.L. PollardW.T. BanksJ.L. J. Med. Chem.20044771750175910.1021/jm030644s15027866
     [Google Scholar]
  66. FriesnerR.A. BanksJ.L. MurphyR.B. HalgrenT.A. KlicicJ.J. MainzD.T. RepaskyM.P. KnollE.H. ShelleyM. PerryJ.K. ShawD.E. FrancisP. ShenkinP.S. J. Med. Chem.20044771739174910.1021/jm030643015027865
     [Google Scholar]
  67. FerreiraL. dos SantosR. OlivaG. AndricopuloA. Molecules2015207133841342110.3390/molecules20071338426205061
     [Google Scholar]
  68. SaghaliM. LemeskiE.T. BaraghooshM.F. MirzaeiH. KhandooziS.R. Erfani-MoghadamV. TazikiS. SoltaniA. Chemical Physics Impact2023710035610.1016/j.chphi.2023.100356
     [Google Scholar]
  69. MoussaN. HassanA. GharaghaniS. Heliyon202174e0660510.1016/j.heliyon.2021.e0660533889764
     [Google Scholar]
  70. PriyaD. KathiravanM.K. J. Biomol. Struct. Dyn.202139145093510410.1080/07391102.2020.178532932602808
     [Google Scholar]
  71. RáczA. BajuszD. HébergerK. SAR QSAR Environ. Res.201829966167410.1080/1062936X.2018.150577830160175
     [Google Scholar]
  72. CoutsiasE.A. WesterM.J. J. Comput. Chem.201940151496150810.1002/jcc.2580230828834
     [Google Scholar]
  73. DammK.L. CarlsonH.A. Biophys. J.200690124558457310.1529/biophysj.105.06665416565070
     [Google Scholar]
  74. LiJ. FuA. ZhangL. Interdiscip. Sci.201911232032810.1007/s12539‑019‑00327‑w30877639
     [Google Scholar]
  75. Carter-FenkK. LiuM. PujalL. LoipersbergerM. TsanaiM. VernonR.M. Forman-KayJ.D. J. Am. Chem. Soc.202314545248362485110.1021/jacs.3c0919837917924
     [Google Scholar]
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Pharmacophore Optimization using Pharmacophore Mapping, QSAR, Docking, and ADMET Screening of Novel Pyrimidines Derivatives as Anticancer DNA Inhibitors
Lett. Org. Chem. 22, 37 (2025); https://doi.org/10.2174/0115701786301475240503071147
/content/journals/loc/10.2174/0115701786301475240503071147
/content/journals/loc/10.2174/0115701786301475240503071147
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  • Article Type:     Research Article
Keyword(s): 3D QSAR; ADME; DNA inhibitor; molecular docking; N-alkyl bromide derivatives; pharmacophore mapping

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