Document Type : Original Article


Department of Chemistry, Bangladesh University of Engineering and Technology, Dhaka-1000, Bangladesh


Background: The carcinogenic kinase PAK1 (p21-activated kinase 1) is associated with the progression of many disorders, including Alzheimer's disease, various cancers, type-2 diabetes and hypertension. Although few synthetic PAK1 inhibitors and herbal therapeutics, such as propolis and curcumin, are available in the market, a comprehensive remedy of PAK1 related ailments is still not studied in detail. Recently, several phthalimide-metal complexes (viz. Λ-FL172, Λ-FL411, called optically active octahedral ruthenium phthalimide complex) were shown as poor inhibition potency toward PAK1. However, for a full understanding of the inhibition of PAK1 about phthalimide analogues, this study has been designed.
Methods: This manuscript presents density functional theory (DFT) based computational approaches of aryl derivatives of phthalimide. The DFT was used to calculate the equilibrium geometries, thermodynamic analysis, dipole moment, polarizability, electrostatic potential map, Mulliken, Hirshfeld, NBO population analysis, frontier molecular orbital contribution, reactivity descriptor, Fukui function analysis of phthalimide derivatives. Molecular docking and ADMET prediction were also performed.
Result: The phthalimide derivatives were subjected to molecular docking studies, and binding affinities ranging from -7.3 to -7.7 kcal/mol against PAK1 kinase were determined. The docked ligands demonstrated stronger hydrogen bonding, electrostatic interactions, and hydrophobic interactions with PAK1 kinase. The magnitude of these contacts usually related with bond lengths and attraction forces. The derivatives with an elevated docking score were chosen against ADMET in silico, and they have an excellent oral bioavailability without observed carcinogenesis or mutagenicity affect.
Conclusion: These results reveal that these phthalimide derivatives might be potential inhibitors for the protein kinase PAK1.

Graphical Abstract

Theoretical Evaluation of 5, 6-Diaroylisoindoline-1,3-dione as Potential Carcinogenic Kinase PAK1 Inhibitor: DFT Calculation, Molecular Docking Study and ADMET Prediction


Main Subjects

1. Sells M A, Knaus U G, Bagrodia S, Ambrose D M, Bokoch G M, Chernoff J. (1997). Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Current Biology, 7(3): 202-210.
2. Delorme V, Machacek M, DerMardirossian C, Anderson K L, Wittmann T, Hanein D, Waterman-Storer C, Danuser G, Bokoch G M. (2007). Cofilin activity downstream of Pak1 regulates cell protrusion efficiency by organizing lamellipodium and lamella actin networks. Developmental cell, 13(5): 646-662.
3. Adam L, Vadlamudi R, Kondapaka S B, Chernoff J, Mendelsohn J, Kumar R. (1998). Heregulin regulates cytoskeletal reorganization and cell migration through the p21-activated kinase-1 via phosphatidylinositol-3 kinase. Journal of Biological Chemistry, 273(43): 28238-28246.
4. Manser E, Leung T, Salihuddin H, Zhao Z-s, Lim L. (1994). A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature, 367(6458): 40-46.
5. Ma Q-L, Yang F, Frautschy S A, Cole G M. (2012). PAK in Alzheimer disease, Huntington disease and X-linked mental retardation. Cellular logistics, 2(2): 117-125.
6. Mendoza-Naranjo A, Gonzalez-Billault C, Maccioni R B. (2007). Aβ1-42 stimulates actin polymerization in hippocampal neurons through Rac1 and Cdc42 Rho GTPases. Journal of cell science, 120(2): 279-288.
7. Arber S, Barbayannis F A, Hanser H, Schneider C, Stanyon C A, Bernard O, Caroni P. (1998). Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature, 393(6687): 805-809.
8. Yang N, Higuchi O, Ohashi K, Nagata K, Wada A, Kangawa K, Nishida E, Mizuno K. (1998). Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature, 393(6687): 809-812.
9. Heredia L, Helguera P, de Olmos S, Kedikian G, Vigo F S, LaFerla F, Staufenbiel M, de Olmos J, Busciglio J, Cáceres A. (2006). Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid β-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer's disease. Journal of Neuroscience, 26(24): 6533-6542.
10. Madzelan P, Labunska T, Wilson M A. (2012). Influence of peptide dipoles and hydrogen bonds on reactive cysteine pK a values in fission yeast DJ‐1. The FEBS journal, 279(22): 4111-4120.
11. Balasenthil S, Sahin A A, Barnes C J, Wang R-A, Pestell R G, Vadlamudi R K, Kumar R. (2004). p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells. Journal of Biological Chemistry, 279(2): 1422-1428.
12. Jagadeeshan S, Krishnamoorthy Y, Singhal M, Subramanian A, Mavuluri J, Lakshmi A, Roshini A, Baskar G, Ravi M, Joseph L. (2015). Transcriptional regulation of fibronectin by p21-activated kinase-1 modulates pancreatic tumorigenesis. Oncogene, 34(4): 455-464.
13. Kumar R, Gururaj A E, Barnes C J. (2006). p21-activated kinases in cancer. Nature Reviews Cancer, 6(6): 459-471.
14. Radu M, Semenova G, Kosoff R, Chernoff J. (2014). PAK signalling during the development and progression of cancer. Nature Reviews Cancer, 14(1): 13-25.
15. Takahashi H, Nguyen B C Q, Uto Y, Shahinozzaman M, Tawata S, Maruta H. (2017). 1, 2, 3-Triazolyl esterization of PAK1-blocking propolis ingredients, artepillin C (ARC) and caffeic acid (CA), for boosting their anti-cancer/anti-PAK1 activities along with cell-permeability. Drug Discoveries & Therapeutics.
16. Zhou Y, Zhang J, Wang J, Cheng M S, Zhao D M, Li F. (2019). Targeting PAK1 with the Small Molecule Drug AK963/40708899 Suppresses Gastric Cancer Cell Proliferation and Invasion by Downregulation of PAK1 Activity and PAK1‐Related Signaling Pathways. The Anatomical Record, 302(9): 1571-1579.
17. Vamecq J, Bac P, Herrenknecht C, Maurois P, Delcourt P, Stables J P. (2000). Synthesis and anticonvulsant and neurotoxic properties of substituted N-phenyl derivatives of the phthalimide pharmacophore. Journal of medicinal chemistry, 43(7): 1311-1319.
18. Blanck S, Geisselbrecht Y, Kräling K, Middel S, Mietke T, Harms K, Essen L-O, Meggers E. (2012). Bioactive cyclometalated phthalimides: design, synthesis and kinase inhibition. Dalton Transactions, 41(31): 9337-9348.
19. Maksimoska J, Feng L, Harms K, Yi C, Kissil J, Marmorstein R, Meggers E. (2008). Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes. Journal of the American Chemical Society, 130(47): 15764-15765.
20. Wang Y, Huang H, Zhang Q, Zhang P. (2018). Chirality in metal-based anticancer agents. Dalton Transactions, 47(12): 4017-4026.
21. Bollati M, Alvarez K, Assenberg R, Baronti C, Canard B, Cook S, Coutard B, Decroly E, de Lamballerie X, Gould E A. (2010). Structure and functionality in flavivirus NS-proteins: perspectives for drug design. Antiviral research, 87(2): 125-148.
22. Cheong P H-Y, Legault C Y, Um J M, Çelebi-Ölçüm N, Houk K. (2011). Quantum mechanical investigations of organocatalysis: mechanisms, reactivities, and selectivities. Chemical reviews, 111(8): 5042-5137.
23. Houk K N, Cheong P H-Y. (2008). Computational prediction of small-molecule catalysts. Nature, 455(7211): 309-313.
24. Niu S, Huang D-L, Dau P D, Liu H-T, Wang L-S, Ichiye T. (2014). Assessment of quantum mechanical methods for copper and iron complexes by photoelectron spectroscopy. Journal of chemical theory and computation, 10(3): 1283-1291.
25. Meng X-Y, Zhang H-X, Mezei M, Cui M. (2011). Molecular docking: a powerful approach for structure-based drug discovery. Current computer-aided drug design, 7(2): 146-157.
26. Hoque M M, Halim M A, Rahman M M, Hossain M I, Khan M W. (2013). Synthesis and structural insights of substituted 2-iodoacetanilides and 2-iodoanilines. Journal of Molecular Structure, 1054: 367-374.
27. Hoque M M, Halim M A, Sarwar M G, Khan M W. (2015). Palladium‐catalyzed cyclization of 2‐alkynyl‐N‐ethanoyl anilines to indoles: synthesis, structural, spectroscopic, and mechanistic study. Journal of Physical Organic Chemistry, 28(12): 732-742.
28. Pang X, Zhou L, Zhang L, Xu L, Zhang X. (2008). Two rules on the protein-ligand interaction. Nature Precedings: 1-1.
29. Parr R G, Yang W. (1984). Density functional approach to the frontier-electron theory of chemical reactivity. Journal of the American Chemical Society, 106(14): 4049-4050.
30. Politzer P, Truhlar D G. (2013). Chemical applications of atomic and molecular electrostatic potentials: reactivity, structure, scattering, and energetics of organic, inorganic, and biological systems: Springer Science & Business Media.
31. H. Weinstein, S. Maayani, S. Srebrenik, S. Cohen, Sokolovsky M. (1975). A theoretical and experimental study of the semirigid cholinergic agonist 3-acetoxyquinuclidine. Molecular pharmacology, 11(5): 671-689.
32. Lien E J, Guo Z, Ru, Li R, Li, Su C, Tang. (1982). Use of dipole moment as a parameter in drug‐receptor interaction and quantitative structure and activity relationship studies. Journal of pharmaceutical sciences, 71(6): 641-655.
33. Romanelli G, Cafferata L, Castro E. (2000). An improved QSAR study of toxicity of saturated alcohols. Journal of Molecular Structure: THEOCHEM, 504(1-3): 261-265.
34. Hemdan M M, El S, Amira A. (2016). Synthesis of Some New Heterocycles Derived from Novel 2(1, 3 Dioxisoindolin 2 yl) Benzoyl Isothiocyanate. Journal of Heterocyclic Chemistry, 53(2): 487-492.
35. Deb M, Hazra S, Gupta A, Elias A J. (2018). Synthesis of unsymmetrical multi-aroyl derivatives of ferrocene using palladium catalysed oxidative C–H aroylation. Dalton Transactions, 47(21): 7229-7236.
36. Pünner F, Schieven J, Hilt G. (2013). Synthesis of fluorenone and anthraquinone derivatives from aryl-and aroyl-substituted propiolates. Organic Letters, 15(18): 4888-4891.
37. Nie Z D, Qiuping; Peng, Yiyuan;. (2016). Synthesis of 6-aroyl phenanthridines by Fe-catalyzed oxidative radical cyclization of 2-isocyanobiphenyls with benzylic alcohols. Tetrahedron, 72(50): 8350-8357.
38. Parr R G, Pearson R G. (1983). Absolute hardness: companion parameter to absolute electronegativity. Journal of the American Chemical Society, 105(26): 7512-7516.
39. Frisch M T, GW; Schlegel, HB; Scuseria, GE; Robb, MA; Cheeseman, JR; Scalmani, G; Barone, V; Mennucci, B; Petersson, GA;. (2009). Gaussian 09 Revision D. 01, 2009, Gaussian Inc. Wallingford CT, 93.
40. Becke A D. (1992). Density functional thermochemistry. I. The effect of the exchange only gradient correction. The Journal of chemical physics, 96(3): 2155-2160.
41. Mulliken R S. (1935). Electronic structures of molecules XI. Electroaffinity, molecular orbitals and dipole moments. The Journal of chemical physics, 3(9): 573-585.
42. Pearson R G. (1986). Absolute electronegativity and hardness correlated with molecular orbital theory. Proceedings of the National Academy of Sciences, 83(22): 8440-8441.
43. Abu Saleh M, Solayman M, Hoque M M, Khan M A, Sarwar M G, Halim M A. (2016). Inhibition of DNA topoisomerase type IIα (TOP2A) by mitoxantrone and its halogenated derivatives: a combined density functional and molecular docking study. BioMed research international, 2016.
44. Koopmans T. (1934). Über die Zuordnung von Wellenfunktionen und Eigenwerten zu den einzelnen Elektronen eines Atoms. physica, 1(1-6): 104-113.
45. Parr R G, László v. Szentpály, and Shubin Liu. (1999.). “Electrophilicity Index.” Journal of the American Chemical Society, 21(9): 1922–1924.
46. Dykstra C E. (2000). Finding the way through intermolecular forces. Perspective on “Permanent and induced molecular moments and long-range intermolecular forces” Theoretical Chemistry Accounts (pp. 278-280): Springer.
47. Abraham J P, Sajan D, Joe I H, Jayakumar V. (2008). Molecular structure, spectroscopic studies and first-order molecular hyperpolarizabilities of p-amino acetanilide. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 71(2): 355-367.
48. Karamanis P, Pouchan C, Maroulis G. (2008). Structure, stability, dipole polarizability and differential polarizability in small gallium arsenide clusters from all-electron ab initio and density-functional-theory calculations. Physical Review A, 77(1): 013201.
49. Parr R G. (1980). Density functional theory of atoms and molecules Horizons of Quantum Chemistry (pp. 5-15): Springer.
50. Ayers P W, Parr R G. (2000). Variational principles for describing chemical reactions: the Fukui function and chemical hardness revisited. Journal of the American Chemical Society, 122(9): 2010-2018.
51. Yang W, Mortier W J. (1986). The use of global and local molecular parameters for the analysis of the gas-phase basicity of amines. Journal of the American Chemical Society, 108(19): 5708-5711.
52. Blanck S, Maksimoska J, Baumeister J, Harms K, Marmorstein R, Meggers E. (2012). The art of filling protein pockets efficiently with octahedral metal complexes. Angewandte Chemie International Edition, 51(21): 5244-5246.
53. DeLano W L. (2002). The PyMOL user's manual.
54. Guex N, Peitsch M C. (1997). SWISS‐MODEL and the Swiss‐Pdb Viewer: an environment for comparative protein modeling. electrophoresis, 18(15): 2714-2723.
55. Dundas J, Ouyang Z, Tseng J, Binkowski A, Turpaz Y, Liang J. (2006). CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues. Nucleic acids research, 34(suppl_2): W116-W118.
56. Trott O O, Arthur J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2): 455-461.
57. Inc A S. (2013). Discovery Studio Modeling Environment, release 4.0.
58. Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, Lee P W, Tang Y. (2012). admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties: ACS Publications.
59. Daina A, Michielin O, Zoete V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports, 7: 42717.
60. Wilson L Y, Famini G R. (1991). Using theoretical descriptors in quantitative structure-activity relationships: some toxicological indices. Journal of medicinal chemistry, 34(5): 1668-1674.
61. Mulliken R S. (1955). Electronic population analysis on LCAO–MO molecular wave functions. I. The Journal of chemical physics, 23(10): 1833-1840.
62. Demircioğlu Z, Kaştaş Ç A, Büyükgüngör O. (2015). Theoretical analysis (NBO, NPA, Mulliken Population Method) and molecular orbital studies (hardness, chemical potential, electrophilicity and Fukui function analysis) of (E)-2-((4-hydroxy-2-methylphenylimino) methyl)-3-methoxyphenol. Journal of Molecular Structure, 1091: 183-195.
63. Shawon J, Khan A M, Rahman A, Hoque M M, Khan M A K, Sarwar M G, Halim M A. (2018). Molecular recognition of azelaic acid and related molecules with DNA polymerase I investigated by molecular modeling calculations. Interdisciplinary Sciences: Computational Life Sciences, 10(3): 525-537.
64. Rodrı́guez-Spong B, Price C P, Jayasankar A, Matzger A J, Rodrı́guez-Hornedo N r. (2004). General principles of pharmaceutical solid polymorphism: a supramolecular perspective. Advanced drug delivery reviews, 56(3): 241-274.
65. Saha S, Roy R K, Ayers P W. (2009). Are the Hirshfeld and Mulliken population analysis schemes consistent with chemical intuition? International journal of quantum chemistry, 109(9): 1790-1806.
66. Tenderholt A, Langner K, O’Boyle N. (2008). A library for package-independent computational chemistry algorithms. J. Comp. Chem: 839-845.
67. Rahman A, Hoque M M, Khan M A, Sarwar M G, Halim M A. (2016). Non-covalent interactions involving halogenated derivatives of capecitabine and thymidylate synthase: a computational approach. SpringerPlus, 5(1): 146.
68. Uddin N, Ahmed S, Khan A M, Mazharol Hoque M, Halim M A. (2020). Halogenated derivatives of methotrexate as human dihydrofolate reductase inhibitors in cancer chemotherapy. Journal of Biomolecular Structure and Dynamics, 38(3): 901-917.
69. Parr R G C, Pratim K;. (1991). Principle of maximum hardness. Journal of the American Chemical Society, 113(5): 1854-1855.
70. Perlstein J. (2001). The Weak Hydrogen Bond In Structural Chemistry and Biology (International Union of Crystallography, Monographs on Crystallography, 9) By Gautam R. Desiraju (University of Hyderabad) and Thomas Steiner (Freie Universität Berlin). Oxford University Press: Oxford and New York. 1999. xiv+ 507 pp. $150. ISBN 0-19-850252-4: ACS Publications.
71. Wade R C, Goodford P J. (1989). The role of hydrogen-bonds in drug binding. Progress in clinical and biological research, 289: 433-444.
72. Quiñonero D, Garau C, Rotger C, Frontera A, Ballester P, Costa A, Deyà P M. (2002). Anion–π interactions: do they exist? Angewandte Chemie, 114(18): 3539-3542.
73. Estarellas C, Frontera A, Quiñonero D, Deyà P M. (2011). Relevant anion–π interactions in biological systems: The case of urate oxidase. Angewandte Chemie, 123(2): 435-438.
74. Lucas X, Bauzá A, Frontera A, Quinonero D. (2016). A thorough anion–π interaction study in biomolecules: on the importance of cooperativity effects. Chemical science, 7(2): 1038-1050.
75. Takamuku S, Nakano M, Kertesz M. (2017). Intramolecular pancake bonding in helical structures. Chemistry–A European Journal, 23(31): 7474-7482.
76. Lipinski C A, Lombardo F, Dominy B W, Feeney P J. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews, 23(1-3): 3-25.
77. Montanari F, Ecker G F. (2015). Prediction of drug–ABC-transporter interaction—Recent advances and future challenges. Advanced drug delivery reviews, 86: 17-26.
78. Szakács G, Váradi A, Özvegy-Laczka C, Sarkadi B. (2008). The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME–Tox). Drug discovery today, 13(9-10): 379-393.