Theoretical investigations, Molecular Docking, ADMET analysis, Molecular Dynamic Simulation, and Drug-Likeness Scoring of (E)-1-[2-(3,4-Dimethylphenyl) Diazen-2-Ium-1-Yl] Naphthalen-2-Olate as a Corticosteroid Side-Chain-Isomerase Inhibitor

Year 2025, Volume: 9 Issue: 3, 57 - 78, 15.09.2025

Youcef Megrouss , Souheyla Chetioui , Chafika Farah Kaouche , Yahıaouı Salem , Khaled Drim , Zohra Douaa Benyahlou , Mansour Azayez , Sid Ahmed Kaas , Mokhtaria Drıssı , Abdelkader Chouaih

https://doi.org/10.33435/tcandtc.1530717

Cited By: 2

Abstract

In this article, the optimized structure and their associated properties of the (E)-1-[2-(3,4-Dimethylphenyl)diazen-2-ium-1-yl]naphthalen-2-olate compound (EDNO) were obtained and evaluated using The density functional theory DFT at the (B3LYP/6-311G++(d,p)) level in the gas phase, To quantify the intermolecular interactions, Hirshfeld surface(HS) analysis was used, HS and 2D fingerprints indicate H⋅⋅⋅H (52%) and C− H⋅⋅⋅C (26.7%) as the most relevant intermolecular interactions in the crystal packing of EDNO. the reduced density gradient (RDG) method was used to reveal and distinguish between attractive interactions such hydrogen bonds, repulsive interactions and van der Waals interactions. Further, molecular docking, binding free energy calculations, and ADMET prole of the title compound was carried out to determine the binding affinity and toxicity. A 100 ns molecular dynamics (MD) simulation was performed to evaluate the binding stability of the compound EDNO/2WV2 complex using Desmond. Binding free energy of the complex was computed for 100 trajectory frames using the MM-GBSA approach

Keywords

Azo Compounds , Hirshfeld surface analysis , DFT calculations , ADMET; Molecular docking; MD simulation.

Thanks

I would like to thank the management of the Turkish computational and theoretical chemistry journal for its contribution to the dissemination of scientific research worldwide.

References

• [1] S. Benkhaya, S. M’rabet, A. El Harfi, Classifications, properties, recent synthesis and applications of azo dyes, Heliyon 6 (2020) e03271.
• [2] C. Luo, O. Borodin, X. Ji, S. Hou, K.J. Gaskell, X. Fan, J. Chen, T. Deng, R. Wang, J. Jiang, C. Wang, Azo compounds as a family of organic electrode materials for alkali-ion batteries, Proc. Natl. Acad. Sci. U.S.A. 115 (2018) 2004–2009.
• [3] R. Petruskevicius, D. Urbonas, M. Gabalis, A. Balcytis, G. Seniutinas, R. Tomasiunas, V. Getautis, Optical poling of azo-compounds for applications in nanophotonics, in: 2013 15th International Conference on Transparent Optical Networks (ICTON), IEEE, Cartagena, Spain, 2013: pp. 1–4.
• [4] E. Węglarz-Tomczak, Ł. Górecki, Azo dyes–biological activity and synthetic Strategy, Chemik Science-Technique-Market 66 (2012) 1298–1307.
• [5] H. Inac, M. Ashfaq, N. Dege, M. Feizi-Dehnayebi, K.S. Munawar, N.K. Yağcı, E. POYRAZ Çınar, M.N. Tahir, Synthesis, spectroscopic characterizations, single crystal XRD, supramolecular assembly inspection via hirshfeld surface analysis, and DFT study of a hydroxy functionalized schiff base Cu(II) complex, Journal of Molecular Structure 1295 (2024) 136751.
• [6] I. Sayer, N. Dege, H. Ghalla, A. Moliterni, H. Naïli, Crystal structure, DFT studies and thermal characterization of new luminescent stannate (IV) based inorganic-organic hybrid compound, Journal of Molecular Structure 1224 (2021) 129266.
• [7] S. Şahin, N. Dege, Synthesis, characterization, X-ray, HOMO-LUMO, MEP, FT-IR, NLO, Hirshfeld surface, ADMET, boiled-egg model properties and molecular docking studies with human cyclophilin D (CypD) of a Schiff base compound: (E)-1-(5-nitro-2-(piperidin-1-yl)phenyl)-N-(3-nitrophenyl)methanimine, Polyhedron 205 (2021) 115320.
• [8] G. Demirtaş, N. Dege, H. İçbudak, Ö. Yurdakul, O. Büyükgüngör, Experimental and DFT Studies on Poly[di-μ3-acesulfamato-O,O:O′;O′:O,O-di-μ-acesulfamato-O,O; N-di-μ-aqua-dicalcium(II)] Complex, J Inorg Organomet Polym 22 (2012) 671–679.
• [9] E. Banaszak-Leonard, A. Fayeulle, A. Franche, S. Sagadevan, M. Billamboz, Antimicrobial azo molecules: a review, J IRAN CHEM SOC 18 (2021) 2829–2851.
• [10] M. Di Martino, L. Sessa, M. Di Matteo, B. Panunzi, S. Piotto, S. Concilio, Azobenzene as Antimicrobial Molecules, Molecules 27 (2022) 5643.
• [11] N.A. Razali, Z. Jamain, Liquid Crystals Investigation Behavior on Azo-Based Compounds: A Review, Polymers 13 (2021) 3462.
• [12] X. Wang, Introduction, in: Azo Polymers, Springer Berlin Heidelberg, Berlin, Heidelberg, 2017: pp. 1–17.
• [13] S. Hamamci Alisir, N. Dege, R. Tapramaz, Synthesis, crystal structures and characterizations of three new copper(II) complexes including anti-inflammatory diclofenac, Acta Cryst C 75 (2019) 388–397.
• [14] N. Dege, H. İçbudak, E. Adıyaman, Bis(acesulfamato-κ2O4,N)bis¬(3-methyl-pyridine)copper(II), Acta Cryst C 62 (2006) m401–m403.
• [15] R. Pino-Rios, E. Pino, G. Cárdenas-Jirón, Deciphering the origin of the first steps in the degradation of azo dyes: a computational study, Environ Sci Pollut Res 31 (2023) 657–667.
• [16] Ö. Tamer, N. Dege, D. Avcı, Y. Atalay, İ. Özer İlhan, M. Çadır, Synthesis, structural and spectroscopic evaluations and nonlinear optical properties of 3,5-bis(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioic O-acid, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 137 (2015) 1387–1396.
• [17] Ö. Tamer, N. Dege, G. Demirtaş, D. Avcı, Y. Atalay, M. Macit, A.A. Ağar, An experimental and theoretical study on the novel (Z)-1-((naphthalen-2-ylamino)methylene)naphthalen-2(1H)-one crystal, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 13–23.
• [18] Dotse Selali Chormey, B.T. Zaman, E. Maltepe, Ç. Büyükpınar, A.E. Bulgurcuoğlu, F. Turak, F.A. Erulaş, S. Bakırdere, Simultaneous Determination of Harmful Aromatic Amine Products of Azo Dyes by Gas Chromatography–Mass Spectrometry, J Anal Chem 75 (2020) 1330–1334.
• [19] N. Dege, M.A. Raza, O.E. Doğan, T. Ağar, M.W. Mumtaz, Theoretical and experimental approaches of new Schiff bases: efficient synthesis, X-ray structures, DFT, molecular modeling and ADMET studies, J IRAN CHEM SOC 18 (2021) 2345–2368.
• [20] F.E. Kalai, E.B. Çınar, C.-H. Lai, S. Daoui, T. Chelfi, M. Allali, N. Dege, K. Karrouchi, N. Benchat, Synthesis, spectroscopy, crystal structure, TGA/DTA study, DFT and molecular docking investigations of (E)-4-(4-methylbenzyl)-6-styrylpyridazin-3(2H)-one, Journal of Molecular Structure 1228 (2021) 129435.
• [21] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, and D. J. Fox, Gaussian, Inc., Wallingford CT, (2016) (n.d.).
• [22] R.D.T.K.J. Millam, Shawnee Mission KS. GaussView, Semichem Inc. (2009). (n.d.).
• [23] P.R. Spackman, M.J. Turner, J.J. McKinnon, S.K. Wolff, D.J. Grimwood, D. Jayatilaka, M.A. Spackman, CrystalExplorer: a program for Hirshfeld surface analysis, visualization and quantitative analysis of molecular crystals, J Appl Cryst 54 (2021) 1006–1011.
• [24] T. Lu, F. Chen, Multiwfn: A multifunctional wavefunction analyzer, J Comput Chem 33 (2012) 580–592.
• [25] W. Humphrey, A. Dalke, K. Schulten, VMD: Visual molecular dynamics, Journal of Molecular Graphics 14 (1996) 33–38.
• [26] O. Trott, A.J. Olson, AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, J Comput Chem 31 (2010) 455–461.
• [27] G.M. Morris, R. Huey, W. Lindstrom, M.F. Sanner, R.K. Belew, D.S. Goodsell, A.J. Olson, AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility, Journal of Computational Chemistry 30 (2009) 2785–2791.
• [28] BIOVIA, Life Sciences and Material Sciences | BIOVIA – Dassault Systèmes. Https://Www.3ds.Com/Products-Services/Biovia/(Accessed June 6, 2022) (n.d.).
• [29] B. Dziuk, B. Ośmiałowski, A. Skotnicka, K. Ejsmont, B. Zarychta, 2-[4-(Dimethylamino)phenyl]-3,3-difluoro-3 H -naphtho[1,2- e ][1,3,2]oxazaborinin-2-ium-3-uide, IUCrData 2 (2017) x171141.
• [30] M.J. Márquez, M.B. Márquez, P.G. Cataldo, S.A. Brandán, A Comparative Study on the Structural and Vibrational Properties of Two Potential Antimicrobial and Anticancer Cyanopyridine Derivatives, OJSTA 04 (2015) 1–19.
• [31] A. Dhandapani, S. Veeramanikandan, R.S. Kumar, A.I. Almansour, N. Arumugam, S. Subashchandrabose, J. Suresh, R. Arulraj, D. Gajalakshmi, Synthesis, in vitro and in silico antitumor evaluation of 3-(2,6-dichlorophenyl)-1,5-diphenylpentane-1,5 dione: Structure, spectroscopic, RDG, Hirshfeld and DFT based analyses, Journal of Molecular Structure 1251 (2022) 132002.
• [32] P. Agarwal, S. Bee, A. Gupta, P. Tandon, V.K. Rastogi, S. Mishra, P. Rawat, Quantum chemical study on influence of intermolecular hydrogen bonding on the geometry, the atomic charges and the vibrational dynamics of 2,6-dichlorobenzonitrile, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 121 (2014) 464–482.
• [33] E.R. Johnson, S. Keinan, P. Mori-Sánchez, J. Contreras-García, A.J. Cohen, W. Yang, Revealing Noncovalent Interactions, J. Am. Chem. Soc. 132 (2010) 6498–6506.
• [34] M.A. Spackman, P.G. Byrom, A novel definition of a molecule in a crystal, Chemical Physics Letters 267 (1997) 215–220.
• [35] M. Ashfaq, K.S. Munawar, G. Bogdanov, A. Ali, M.N. Tahir, G. Ahmed, A. Ramalingam, M.M. Alam, M. Imran, S. Sambandam, B. Munir, Single crystal inspection, Hirshfeld surface investigation and DFT study of a novel derivative of 4-fluoroaniline: 4-((4-fluorophenyl)amino)-4-oxobutanoic acid (BFAOB), J IRAN CHEM SOC 19 (2022) 1953–1961.
• [36] P.R. Spackman, M.J. Turner, J.J. McKinnon, S.K. Wolff, D.J. Grimwood, D. Jayatilaka, M.A. Spackman, CrystalExplorer: a program for Hirshfeld surface analysis, visualization and quantitative analysis of molecular crystals, J Appl Cryst 54 (2021) 1006–1011.
• [37] M.A. Spackman, J.J. McKinnon, Fingerprinting intermolecular interactions in molecular crystals, CrystEngComm 4 (2002) 378–392.
• [38] S.A. Kaas, F.T. Baara, Y. Megrouss, S. Yahiaoui, A. Djafri, F.Z. Boudjenane, A. Chouaih, A. Djafri, A. Hatzidimitriou, Synthesis, crystal structure, Hirshfeld surface analysis, computational investigations and molecular docking studies of (Z)-3-N-(methyl)-2-N’-(4-methoxyphenylimino) thiazolidin-4-one dihydrate, Journal of Molecular Structure 1308 (2024) 137964.
• [39] S. Yahiaoui, Y. Megrouss, N. Boukabcha, N. El Houda Belkafouf, N. Khelloul, R. Rahmani, N. Boubegra, A. Chouaih, Structural characterization, molecular docking assessment, drug-likeness study and DFT investigation of 2-(2-{1,2-dibromo-2-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-fluoro-ethyl1}-phenyl)-methyl 3-methoxy-acrylic ester, Journal of the Indian Chemical Society 99 (2022) 100745.
• [40] S. Akash, F.I. Aovi, Md.A.K. Azad, A. Kumer, U. Chakma, Md.R. Islam, N. Mukerjee, Md.M. Rahman, I. Bayıl, S. Rashid, R. Sharma, A drug design strategy based on molecular docking and molecular dynamics simulations applied to development of inhibitor against triple-negative breast cancer by Scutellarein derivatives, PLoS ONE 18 (2023) e0283271.
• [41] A.A. Basha, A. Kubaib, M. Azam, Exploring the antiviral potency of γ-FP and PA compounds: Electronic characterization, non-covalent interaction analysis and docking profiling with emphasis on QTAIM aspects, Computational and Theoretical Chemistry 1231 (2024) 114412.
• [42] M.C. Walker, A. Marandici, K. Martin, C. Monder, Genetic Control of Corticosteroid Side-Chain Isomerase Activity in the Mouse*, Endocrinology 112 (1983) 924–930.
• [43] C. Monder, A. Marandici, Corticosteroid side-chain isomerase in the circulatory system, Steroids 56 (1991) 12–16.
• [44] L.A.R. Sallam, A.-M. El-Refai, H.A. El-Minofi, Physiological and biochemical improvement of the enzyme side-chain degradation of cholesterol by Fusarium solani, Process Biochemistry 40 (2005) 203–206.
• [45] M. Mutsuga, Y. Asaoka, N. Imura, T. Miyoshi, Y. Togashi, Aminoglutethimide-induced lysosomal changes in adrenal gland in mice, Experimental and Toxicologic Pathology 69 (2017) 424–429.
• [46] H. Ferjani, R. Bechaieb, N. Dege, W.A. El-Fattah, N.Y. Elamin, W. Frigui, Stabilization of supramolecular network of fluconazole drug polyiodide: Synthesis, computational and spectroscopic studies, Journal of Molecular Structure 1263 (2022) 133192.
• [47] X. Qi, Y. Zhao, Z. Qi, S. Hou, J. Chen, Machine Learning Empowering Drug Discovery: Applications, Opportunities and Challenges, Molecules 29 (2024) 903.
• [48] M. Mandal, S. Mandal, MM/GB(PB)SA integrated with molecular docking and ADMET approach to inhibit the fat-mass-and-obesity-associated protein using bioactive compounds derived from food plants used in traditional Chinese medicine, Pharmacological Research - Modern Chinese Medicine 11 (2024) 100435.
• [49] J. Dulsat, B. López-Nieto, R. Estrada-Tejedor, J.I. Borrell, Evaluation of Free Online ADMET Tools for Academic or Small Biotech Environments, Molecules 28 (2023) 776.
• [50] V. Manakkadan, J. Haribabu, V.N.V. Palakkeezhillam, P. Rasin, M. Mandal, V.S. Kumar, N. Bhuvanesh, R. Udayabhaskar, A. Sreekanth, Synthesis and characterization of N-substituted thiosemicarbazones: DNA/BSA binding, molecular docking, anticancer activity, ADME study and computational investigations, Journal of Molecular Structure 1285 (2023) 135494.
• [51] Z. Fralish, A. Chen, P. Skaluba, D. Reker, DeepDelta: predicting ADMET improvements of molecular derivatives with deep learning, J Cheminform 15 (2023) 101.
• [52] C.M. Chagas, S. Moss, L. Alisaraie, Drug metabolites and their effects on the development of adverse reactions: Revisiting Lipinski’s Rule of Five, International Journal of Pharmaceutics 549 (2018) 133–149.
• [53] R.N. Sahoo, S. Pattanaik, G. Pattnaik, S. Mallick, R. Mohapatra, Review on the use of Molecular Docking as the First Line Tool in Drug Discovery and Development, IJPS 84 (2022).
• [54] P.C. Agu, C.A. Afiukwa, O.U. Orji, E.M. Ezeh, I.H. Ofoke, C.O. Ogbu, E.I. Ugwuja, P.M. Aja, Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management, Sci Rep 13 (2023) 13398.
• [55] H.M. Berman, The Protein Data Bank, Nucleic Acids Research 28 (2000) 235–242.
• [56] C.-K. Chen, S.S.F. Leung, C. Guilbert, M.P. Jacobson, J.H. McKerrow, L.M. Podust, Structural Characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei Bound to the Antifungal Drugs Posaconazole and Fluconazole, PLoS Negl Trop Dis 4 (2010) e651.
• [57] I. Sama-ae, N.C. Pattaranggoon, A. Tedasen, In silico prediction of Antifungal compounds from Natural sources towards Lanosterol 14-alpha demethylase (CYP51) using Molecular docking and Molecular dynamic simulation, Journal of Molecular Graphics and Modelling 121 (2023) 108435.
• [58] R. Zhang, Y. Wang, A. Wu, J. Wang, J. Zhang, Strategies of targeting CYP51 for IFIs therapy: Emerging prospects, opportunities and challenges, European Journal of Medicinal Chemistry 259 (2023) 115658.
• [59] N. Khelfa, S. Belaidi, O. Abchir, I. Yamari, S. Chtita, A. Samadi, M.M. Al-Mogren, M. Hochlaf, Combined 3D-QSAR, molecular docking, ADMET, and drug-likeness scoring of novel diaminodihydrotriazines as potential antimalarial agents, Scientific African 24 (2024) e02202.
• [60] K.J. Bowers, F.D. Sacerdoti, J.K. Salmon, Y. Shan, D.E. Shaw, E. Chow, H. Xu, R.O. Dror, M.P. Eastwood, B.A. Gregersen, J.L. Klepeis, I. Kolossvary, M.A. Moraes, Molecular dynamics---Scalable algorithms for molecular dynamics simulations on commodity clusters, in: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing - SC ’06, ACM Press, Tampa, Florida, 2006: p. 84.
• [61] E. Harder, W. Damm, J. Maple, C. Wu, M. Reboul, J.Y. Xiang, L. Wang, D. Lupyan, M.K. Dahlgren, J.L. Knight, J.W. Kaus, D.S. Cerutti, G. Krilov, W.L. Jorgensen, R. Abel, R.A. Friesner, OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins, J. Chem. Theory Comput. 12 (2016) 281–296.
• [62] C.C. David, D.J. Jacobs, Principal Component Analysis: A Method for Determining the Essential Dynamics of Proteins, in: D.R. Livesay (Ed.), Protein Dynamics, Humana Press, Totowa, NJ, 2014: pp. 193–226.
• [63] M.P. Jacobson, D.L. Pincus, C.S. Rapp, T.J.F. Day, B. Honig, D.E. Shaw, R.A. Friesner, A hierarchical approach to all‐atom protein loop prediction, Proteins 55 (2004) 351–367.
• [64] M.P. Jacobson, R.A. Friesner, Z. Xiang, B. Honig, On the Role of the Crystal Environment in Determining Protein Side-chain Conformations, Journal of Molecular Biology 320 (2002) 597–608.