2,4-SUBSTITUTED QUINAZOLINE AS JAK2 INHIBITOR: DOCKING AND MOLECULAR DYNAMICS STUDY
Objective: The involvement of Janus kinase2/signal transducer and activator of transcription (JAK2/STAT3) pathway reported in various solid tumors made authors study the conformational changes of JAK2-3e complex which was previously reported with a moderate percentage of In-vitro JAK2 inhibition.
Methods: In this present study Compound 3e was reported with a moderate percentage of inhibition of JAK2 protein selected for performing molecular docking and molecular dynamics studies to elucidate the conformational changes with JAK2-3e complex. Docking studies were performed using ChemSketch to draw the structure of the compound and optimized/energy minimized using the Ligprep module of Schrodinger suite, employing optimized potentials for liquid simulations (OPLS-2005) force field. Molecular dynamics simulations were performed for 10 ns for complex using TIP4PEW water solvent model and neutralized by adding sodium ions.
Results: Docking studies of Compound 3e which has been reported as one of the effective cytotoxic agents and a moderate percentage of In-vitro JAK2 inhibition among the series, showed H-bond interaction with leucine 855, serine936, aspartine994. Dock score and Ligand binding energy with protein suggested compound 3e has shown-4.049,-66.003 kcal/mol respectively. Molecular dynamics simulations elucidated the mechanistic insight of JAK-2 inhibition. The Root means square deviation (RMSD) pattern of both protein and ligands in the JAK2-3e complex observed to be different over 10 ns simulation. In the JAK2-3e complex, an exponential increase in RMSD of Cα and side-chain amino acids is observed during the first 1-3 ns simulation and is stabilized till 10 ns. During the 10 ns simulation, ligand 3e seems to be stable in the complex with an overall deviation<1 Å, despite a drastic increase between 1-3 ns. The ligand RMSD plot suggests that the ligand 3e remained intact within the binding site of the protein and longer time period simulation may elucidate the binding pattern and fate of ligand 3e.
Conclusion: Results from molecular dynamics simulations elucidated the mechanistic insight of JAK-2 inhibition by 2, 4 disubstituted quinazoline compound that is N’(2-(4-nitrophenyl)quinazoline-4-yl) isonicotinohydrazide) and their binding phenomenon. Molecular docking studies further supported the elucidation of binding patterns of the molecules in the JAK-2 protein environment. Further simulations with a longer time period may provide deeper insights into ligand interactions in the protein environment. It is noteworthy to use compound 3e as a new scaffold for further development of multifunctional compounds.
2. Rania SM Ismail. Recent advances in 4-Amino quinazoline based scaffold derivatives targeting EGFR kinases as anticancer agents. Future J Pharm Sci 2016:2:9-19.
3. Jatav V, Kashaw S, Mishra P. Synthesis and antimicrobial activity of some new 3–[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2-styrylquinazoline-4(3H)-ones. Med Chem Res 2008:17:205–11.
4. Leena KP, Subin MZ, Deepthy CH. In silico design, synthesis and characterization of some novel benzothiazole derivatives as anticancer agents. Asian J Pharm Clin Res 2017;10:500-15.
5. Priya D, Srimathi R, Anjana GV. Synthesis and evaluation of some mannich bases of the quinazolinone nucleus. Asian J Pharm Clin Res 2018;11:407-9.
6. Chandregowda V, Kush AK, Chandrasekara Reddy G. Synthesis and in vitroantitumor activities of novel 4-anilinoquinazoline derivatives. Eur J Med Chem 2009;44:3046–55.
7. Al-Rashood ST, Aboldahab IA, Nagi MN, Abouzeid LA, Abdel-Aziz AA, Abdel-Hamide SG, et al. Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs. Bioorg Med Chem 2006;14:8608–21.
8. Oshealji J. The JAK-STAT pathway, impact on human disease and therapeutic invention. Annu Rou Med 2015;66:311-28.
9. Liongue C, Sertori R, Ward AC. Evolution of cytokine receptor signaling. J Immunol 2016;197:11-8.
10. George Speyer Hans. Jak stat signaling and cancer; opportunities, benefits and side effects of targeted inhibition. Mol Cell Endocrinol 2017;45:1-14.
11. Shagufta. An insight therapeutic potential of quinazoline derivatives as anticancer agents. Med Chem Commun 2017;8:1-26.
12. Ahmad I, Shagufta. Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer. Eur J Med Chem 2015;102:375-86.
13. Ahmad I, Shagufta. Sulfones: an important class of organic compounds with diverse biological activities. Int J Pharm Sci 2015;7:19-27.
14. Demeunynck M, Baussanne I. Survey of recent literature related to the biologically active 4(3H)-quinazolinones containing fused heterocycles. Curr Med Chem 2013;20:794–814.
15. Raghavendra NM, Thampi P, Guru Basavaraja Swami PM, Sriram D. Synthesis and antimicrobial activities of some novel substituted 2-imidazolyl-N-(4-oxo-quinazolin-3(4H)-yl)-acetamides. Chem Pharm Bull 2007;55:1615-9.
16. Paneersalvam P, Rather BA, Reddy DRS, Kumar NR. Synthesis and anti-microbial screening of some Schiff bases of 3-amino-6,8-dibromo-2-phenylquinazolin-4(3H)-ones. Eur J Med Chem 2009;44:2328-33.
17. Verhaeghe P, Azas N, Gasquet M, Hutter S, Ducros C, Laget M, et al. Synthesis and antiplasmodial activity of new 4-aryl-2-trichloromethylquinazolines. Bioorg Med Chem Lett 2008;18:396-401.
18. Saravanan G, Paneersalvam P, Prakash CR. Synthesis, analgesic and anti-inflammatory screening of novel Schiff bases of 3-amino-2-methyl quinazoline 4-(3H)-one. Der Pharm Lett 2010;2:216-26.
19. Alagarsamy V, Solomon VR, Sheorey RV, Jayakumar R. 3-(3-Ethylphenyl)-2-substitutedhydrazino-3H-quinazolin-4-one derivatives: new class of analgesic and anti-inflammatory agents. Chem Biol Drug Des 2009;73:471-9.
20. Smits RA, Adami M, Istyastono EP, Zuiderveld OP, van Dam CME. Synthesis and QSAR of quinazoline sulfonamide as highly potent human histamine H4 receptor inverse agonists. J Med Chem 2010;53:2390-400.
21. Georgey H, Abdel Gawad N, Abbas S. Synthesis and anticonvulsant activity of some quinazoline-4-(3H)-one derivatives. Molecules 2008;13:2557-69.
22. Patel NB. Synthesis and microbial studies of (4-oxo-thiazolidinyl) sulfonamides bearing quinazolin-4(3H) ones. Acta Polo Pharm Drug Res 2010;67:267-75.
23. Ismail MAH, Barker S, Abau El Ella DA, Abouzid KAM, Toubar RA. Design and synthesis of new tetrazolyl-and carboxy-biphenylylmethyl-quinazolin-4-one derivatives as angiotensin II AT1 receptor antagonists. J Med Chem 2006;49:1526-35.
24. Zaranappa, Vagdevi HM, Lokesh MR, Gowdarshivannanava BC. Synthesis and antioxidant activity of 3-substituted schiff bases of quinazoline-2,4-diones. Int J Chem Tech Res 2012;4:1527-33.
25. Krishnan SK. Synthesis, antiviral and cytotoxic investigation of 2-phenyl-3-substituted quinazolin-4(3H)-ones. Eur Rev Med Pharm Sci 2011;15:673–81.
26. Pati B, Banerjee S. Quinazolines: an illustrated review. J Adv Pharm Edu Res 2013;3:136-51.
27. Katrin SN. Chemotherapy and dietary phytochemical agents. Chemother Res Prac 2012;3:22–7.
28. Manasa AK, Sidhaye RV, Radhika G, Nalini CN. Synthesis, antioxidant and anticancer activity of quinazoline derivatives. Curr Pharma Res 2011;1:101-5.
29. Nerkar B, Saxena A, Ghone S, Thakeri AK. In silico screening, synthesis and in vitro evaluation of some quinazolinone and pyridine derivatives as dihydrofolate reductase inhibitors for anticancer activity. E-J Chem 2009;6:97-102.
30. Ahmed MF, Youns M. Synthesis and biological evaluation of a novel series of 6, 8?Dibromo?4 (3H) quinazolinone derivatives as anticancer agents. Archiv Der Pharmazie 2013;346:610-7.
31. Moon DO, Kim MO, Heo MS, Lee JD, Choi YH, Kim GY. Gefitinib induces apoptosis and decreases telomerase activity in MDA-MB-231 human breast cancer cells. Arch Pharm Res 2009;32:1351-60.
32. Sirisoma N, Pervin A, Zhang H, Jiang S, Adam Willardsen J. Discovery of N-methyl-4-(4-methoxyanilino)quinazolines as potent apoptosis inducers. Structure-activity relationship of the quinazoline ring. Bioorg Med Chem Lett 2010;20:2330-4.
33. Font M, Gonzalez A, Palop JA, Sanmartin C. New insights into the structural requirements for pro-apoptotic agents based on 2,4-diaminoquinazoline, 2,4-diaminopyrido[2,3-d]pyrimidine and 2,4-diaminopyrimidine derivatives. Eur J Med Chem 2011;46:3887-99.
34. Liu F, Lovejoy DB, Hassani AA, He Y, Herold JM, Chen X, et al. Optimization of cellular activity of G9aInhibitors 7-aminoalkoxy-quinazolines. J Med Chem 2011;54:6139-50.
35. EI-Azab AS, Al-Omar MA, Abdel Aziz AA Metal. Design, synthesis and biological evaluation of novel quinazoline derivatives as potential antitumor agents: molecular docking study. Eur J Med Chem 2010;45:4188-98.
36. Al-Obaid AM, Abdel-Hamide SGA, El-Kashef HA. Substituted quinazolines, part 3. Synthesis, in vitro antitumor activity and molecular modeling study of certain 2-thieno-4(3H)-quinazolinone analogs. Eur J Med Chem 2009;44:2379-91.
37. Alafeefy AM, Kadi AA, El-Azab AS, Abdel-Hamide SG, Daba MH. Synthesis, analgesic and anti-inflammatory evaluation of some new 3H-quinazolin-4-one derivatives. Archiv Der Pharmazie 2008;341:377-85.
38. Kumar A, Sharma S, Archana A, Bajaj K, Sharma Setal. Some new 2,3,6-trisubstituted quinazolinones as a potent anti-inflammatory, analgesic and COX-II inhibitors. Bioorg Med Chem 2003;11:5293-9.
39. El-Azab AS, Kamal EH. Design and synthesis of novel 7-aminoquinazoline derivatives: antitumor and anticonvulsant activities. Bioorg Med Chem Lett 2012;22:1879-85.
40. Kashaw SK, Kashaw V, Mishra P, Jain NK, Stables JP. Synthesis, anticonvulsant and CNS depressant activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea. Eur J Med Chem 2009;44:4335-43.
41. Archana V, Srivastava K, Kumar A. Synthesis of some newer derivatives of substitutedquinazolinonyl-2-oxo/thiobarbituric acid as potent anticonvulsant agents. Bioorg Med Chem 2004;12:1257-64.
42. Al-Suwaidan IA, Alanazi AM, Abdel-Aziz AA, Mohamed MA, El-Azab AS. Design, synthesis and biological evaluation of 2-mercapto-3-phenethylquinazoline bearing anilide fragments as potential antitumor agents: molecular docking study. Bioorg Med Chem Lett 2013;23:3935-41.
43. Abdel Gawad NM, Georgey HH, Youssef RM, El-Sayed NA. Synthesis and antitumor activity of some 2, 3-disubstituted quinazolin-4(3H)-ones and 4, 6-disubstituted-1, 2, 3, 4-tetrahydro quinazoline-2H-ones. Eur J Med Chem 2010;45:6058-67.
44. B Siva Jyothi, MC Paturi, H Perka, DR Gade, VVS Rajendra Prasad. Novel 2,4-disubstituted quinazolines as cytotoxic agents and JAK2 inhibitors: synthesis, in vitro evaluation and molecular dynamics studies. Comput Biol Chem 2019;79:110-8.
45. VVS Rajendra Prasad, DR Gade, D Appaji, GJ Peters, YC Mayur. Chemosensitizing acridones: in vitro calmodulin-dependent cAMP phosphodiesterase inhibition, docking, pharmacophore modeling, and 3D QSAR studies. J Mol Graph Model 2013;40:116-24.
46. VVS Rajendra Prasad, DR Gade, I Kathmann, M Amareswararao, GJ Peters. Nitric oxide-releasing acridone carboxamide derivatives as reverters of doxorubicin resistance in MCF7/Dx cancer cells. Bioorg Chem 2016;64:51-8.
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