Computational analysis using ADMET profiling, DFT calculations and molecular docking of two anti-cancer drugs

Year 2023, Volume: 7 Issue: 1, 37 - 50, 15.01.2023

Anaridha S. , Mohamed Imran P K , Khaja Mohideen A , Salım Meeran I , Shabeer T. K.

https://doi.org/10.33435/tcandtc.1102295

Cited By: 3

Abstract

U.S. FDA approved anti-cancer drugs, namely ribociclib and copanlisib used for treating breast cancer and follicular lymphoma, respectively, were chosen for computational study. Quantum chemical calculations via DFT and MP2 were used for energy optimization of the drugs. Chemical descriptor parameters were compared between DFT and MP2 values for each atom, and the most reactive and stable atoms were reported. To describe the reactivity and stability of the drug molecules, Fukui functions were calculated. Molecular docking of the drugs was performed against epidermal growth factor receptor (EGFR) and cellular inhibitor of apoptosis protein-1 (cIAP1) receptor proteins to study the drug-protein binding interactions. The binding energy values before optimization and after optimization were found to be -11.21 and -14.41 kcal.mol-1 for copanlisib and -13.58 kcal and -29.08 kcal for ribociclib respectively. Atoms O27 and O10 are reported to be the most reactive atom based on high softness value. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the drugs were evaluated using open-source in-silico tools. ADME profiling of drug molecules indicated good to moderate solubility and low to high absorption in the gastrointestinal tract. Predicted toxicity was class five for both anti-cancer drugs. The structural and bioactive properties of the drugs focused on in this study help evaluate the better reactivity patterns of anticancer medicines.

Keywords

Anti-cancer, ADMET, DFT, Molecular Docking, Fukui Function, HOMO-LUMO.

Supporting Institution

Nil

Project Number

Nil

Thanks

Nil

References

• [1] Masoudkabir, F., Sarrafzadegan, N., Gotay, C., Ignaszewski, A., Krahn, A. D., Davis, M. K., Mani, A. Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention. Atherosclerosis, 263 (2017) 343–351. doi:10.1016/j.atherosclerosis.2017.06.001
• [2] RamdasNayak MBBS MD., Exam Preparatory Manual for Undergraduates-Pathology. Second Edition: 2017.ISBN 978-93-86261-21-2
• [3] Sorlie, T., Perou, C. M., Tibshirani, R., Aas, T., Geisler, S., Johnsen, H., Borresen-Dale, A. L. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proceedings of the National Academy of Sciences, 98(19) (2001) 10869–10874. doi:10.1073/pnas.191367098
• [4] Perou, C. M., Sørlie, T., Eisen, M. B., van de Rijn, M., Jeffrey, S. S., Rees, C. A., Botstein, D. Molecular portraits of human breast tumours. Nature, 406(6797) (2000) 747–752. doi:10.1038/35021093
• [5] Giancotti, F. G. Deregulation of cell signaling in cancer. FEBS Letters, 588(16), (2014) 2558–2570. doi:10.1016/j.febslet.2014.02.005
• [6] Glück, S. Consequences of the Convergence of Multiple Alternate Pathways on the Estrogen Receptor in the Treatment of Metastatic Breast Cancer. Clinical Breast Cancer, 17(2) (2017) 79–90. doi:10.1016/j.clbc.2016.08.004
• [7] Dragani, T. A., Castells, A., Kulasingam, V., Diamandis, E. P., Earl, H., Iams, W. T., Schalken, J. A. Major milestones in translational oncology. BMC Medicine, 14(1) (2016). doi:10.1186/s12916-016-0654-y
• [8] Supreet Kaur Gill, Ajay Francis Christopher, Vikas Gupta, Parveen Bansal. Emerging role of bioinformatics tools and software in evolution of clinical research. Perspectives in Clinical Research 7(3) (2016) 115-122. DOI: 10.4103/2229-3485.184782
• [9] Katsila, T., Spyroulias, G. A., Patrinos, G. P., &Matsoukas, M.-T. Computational approaches in target identification and drug discovery. Computational and Structural Biotechnology Journal, 14 (2016) 177–184. doi:10.1016/j.csbj.2016.04.004
• [10] Karim, S., Al-Maghrabi, J. A., Farsi, H. M. A., Al-Sayyad, A. J., Schulten, H.-J., Buhmeida, A., … Al-Qahtani, M. H. Cyclin D1 as a therapeutic target of renal cell carcinoma- a combined transcriptomics, tissue microarray and molecular docking study from the Kingdom of Saudi Arabia. BMC Cancer, 16(S2) (2016) 741. doi:10.1186/s12885-016-2775-2
• [11] Hiteshi T, Tanmoy C, Vandana S. A Brief Review on Importance of DFT In Drug Design. Res Med Eng Sci. 7(4) (2019). doi: 10.31031/RMES.2019.07.0006
• [12] Ramachandran K. I., DeepaNamboori G., K. Computational Chemistry and Molecular Modeling (2008). doi:10.1007/978-3-540-77304-7
• [13] Tsubomura H, Mullikken R S; J. Am. Chem. Soc., 82 (1960) 5966
• [14] A Thesis submitted by Mohamed Imran P K. Chemical Reactivity Descriptors from Theoretical Methods for structure-property Evaluation of Small Molecules
• [15] Sevvanthi, S., Muthu, S., & Raja, M. Molecular docking, vibrational spectroscopy studies of (RS)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one: A potential adrenaline uptake inhibitor. Journal of Molecular Structure, 1173 (2018) 251–260. doi:10.1016/j.molstruc.2018.07.001
• [16] Ramachandran, K. I., G. Deepa, and K. Namboori. (2008) Computational chemistry and molecular modeling: principles and applications. Berlin: Springer. http://site.ebrary.com/id/10284515
• [17] Chandrakumar, K., & Pal, S. The Concept of Density Functional Theory Based Descriptors and its Relation with the Reactivity of Molecular Systems: A Semi-Quantitative Study. International Journal of Molecular Sciences, 3(4) (2002) 324–337. doi:10.3390/i3040324
• [18] Gross, K. C., & Seybold, P. G. Substituent effects on the physical properties and pKa of aniline. International Journal of Quantum Chemistry, 80(4-5) (2000) 1107–1115. doi:10.1002/1097461x(2000)80:4/5<1107::aid-qua60>3.0.co;2-t
• [19] Fukui, K. (1970). Theory of orientation and stereoselection. In: Orientation and Stereoselection. Fortschritte der ChemischenForschung, vol 15/1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/BFb0051113
• [20] Fukui K; Science, 1982, 218, 747
• [21] Sakthivel, S., Alagesan, T., Muthu, S., Abraham, C. S., & Geetha, E. Quantum mechanical, spectroscopic study (FT-IR and FT - Raman), NBO analysis, HOMO-LUMO, first order hyperpolarizability and docking studies of a non-steroidal anti-inflammatory compound. Journal of Molecular Structure, 1156 (2018) 645–656. doi:10.1016/j.molstruc.2017.12.024
• [22] Fukui, K. (1975). Theory of orientation and stereoselection. In: Orientation and Stereoselection. Fortschritte der ChemischenForschung, vol 15/1. Springer, Berlin, Heidelberg
• [23] Yang, W., Mortier, W. J. 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) (1986) 5708–5711. doi:10.1021/ja00279a008
• [24] Laurent, A. D., &Jacquemin, D. TD-DFT benchmarks: A review. International Journal of Quantum Chemistry, 113(17) (2013) 2019–2039. doi:10.1002/qua.24438
• [25] ACD/ChemSketch, version 2021.1. 1, Advanced Chemistry Development, Inc., Toronto, ON, Canada, www.acdlabs.com, 2021
• [26] Hanwell, M. D., Curtis, D. E., Lonie, D. C., Vandermeersch, T., Zurek, E., & Hutchison, G. R. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics, 4(1) (2012)17. doi:10.1186/1758-2946-4-17
• [27] G. teVelde, F.M. Bickelhaupt, E.J. Baerends, C. Fonseca Guerra, S.J.A. van Gisbergen, J.G. Snijders and T. Ziegler, Chemistry with ADF, Inc. J ComputChem, 22(2001) 931–967, doi: 10.1002/jcc.1056
• [28] Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30(16) (2009) 2785–2791. doi:10.1002/jcc.21256
• [29] Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego: DassaultSystèmes, 2016
• [30] Daina, A., Michielin, O., & Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(1) (2017). doi:10.1038/srep42717
• [31] Banerjee, P., Eckert, A. O., Schrey, A. K., & Preissner, R. ProTox-II: a web server for the prediction of toxicity of chemicals. Nucleic Acids Research, 46(W1) (2018) W257–W263. doi:10.1093/nar/gky318
• [32] Thompson, M.A. (2004) Molecular Docking Using ArgusLab, an Efficient Shape-Based Search Algorithm and a Score Scoring Function. ACS Meeting, Philadelphia
• [33] Zhurko GA, Zhurko DA. Chemcraft Program, Academic version 1.5, 2004
• [34] Gaitonde, Vishwanath; Karmakar, Partha; Trivedi, Ashit (2020). Drug Discovery and Development - New Advances, Molecular Docking in Modern Drug Discovery: Principles and Recent Applications., 10.5772/intechopen.77685(Chapter 3), –. doi:10.5772/intechopen.85991
• [35] Hojjat-Farsangi, M. Small-Molecule Inhibitors of the Receptor Tyrosine Kinases: Promising Tools for Targeted Cancer Therapies. International Journal of Molecular Sciences, 15(8) (2014) 13768–13801. doi:10.3390/ijms150813768
• [36] Murphy, C. G., & Dickler, M. N. The Role of CDK4/6 Inhibition in Breast Cancer. The Oncologist, 20(5) (2015) 483–490. doi:10.1634/theoncologist.2014-0443
• [37] https://go.drugbank.com/drugs/DB12483
• [38] Patnaik, A., Appleman, L. J., Tolcher, A. W., Papadopoulos, K. P., Beeram, M., Rasco, D. W., Ramanathan, R. K. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Annals of Oncology, 27(10) (2016) 1928–1940. doi:10.1093/annonc/mdw282
• [39] Eltantawy, A., Vallejos, X., Sebea, E., & Evans, K. Copanlisib: An Intravenous Phosphatidylinositol 3-Kinase (PI3K) Inhibitor for the Treatment of Relapsed Follicular Lymphoma. Annals of Pharmacotherapy, 53(9) (2019) 954–958. doi:10.1177/1060028019833992
• [40] M. Dreyling, D. Cunningham, K. Bouabdallah, S. Assouline, E. V. den Neste, U. Vitolo, M. Giurescu, S. Mappa, J. Grunert, B. H. Childs and F. Morschhauser, Blood, 124 (2014) 1701. doi:10.1182/blood.V124.21.1701.1701
• [41] Salim Meeran I ,Baskar V., Syed Tajudeen S., Shabeer T. K..Design, ADME Profiling, and Molecular Docking Simulation of New Isoniazid-Schiff Base Analogs as MtKasB Inhibitors. Asian Journal of Research in Chemistry and Pharmaceutical Sciences, 6(1) (2018) 20-34
• [42] Chandrakumar, K., & Pal, S. The Concept of Density Functional Theory Based Descriptors and its Relation with the Reactivity of Molecular Systems: A Semi-Quantitative Study. International Journal of Molecular Sciences, 3(4) (2002) 324–337. doi:10.3390/i3040324
• [43] Gross, K. C., & Seybold, P. G. Substituent effects on the physical properties and pKa of aniline. International Journal of Quantum Chemistry, 80(4-5) (2000) 1107–1115. doi:10.1002/1097-461x(2000)80:4/5<1107::aid-qua60>3.0.co;2-t
• [44] Sakthivel, S., Alagesan, T., Muthu, S., Abraham, C. S., &Geetha, E. Quantum mechanical, spectroscopic study (FT-IR and FT - Raman), NBO analysis, HOMO-LUMO, first order hyperpolarizability and docking studies of a non-steroidal anti-inflammatory compound. Journal of Molecular Structure, 1156 (2018) 645–656. doi:10.1016/j.molstruc.2017.12.024
• [45] Muthu, S., Elamurugu Porchelvi, E., Karabacak, M., Asiri, A. M., &Swathi, S. S. Synthesis, structure, spectroscopic studies (FT-IR, FT-Raman and UV), normal coordinate, NBO and NLO analysis of salicylaldehyde p-chlorophenylthiosemicarbazone. Journal of Molecular Structure, 1081 (2015) 400–412. doi:10.1016/j.molstruc.2014.10.024
• [46] Kuruvilla, T. K., Muthu, S., Prasana, J. C., George, J., &Sevvanthi, S. Spectroscopic (FT-IR, FT-Raman), quantum mechanical and docking studies on methyl[(3S)-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propyl]amine. Journal of Molecular Structure, 1175 (2019) 163–174. doi:10.1016/j.molstruc.2018.07.097
• [47] Tüzün, B.. Investi̇gati̇on of pyrazoly derivatives schi̇ff base li̇gands and thei̇r metal complexes used as anti-cancer drug. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 227 (2020) 117663. doi:10.1016/j.saa.2019.117663
• [48] Bytyqi-Damoni, A., Kestane, A., Taslimi, P., Tuzun, B., Zengin, M., Bilgicli, H. G., & Gulcin, İ. Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization, biological evaluation, and molecular docking studies. Journal of Molecular Structure (2019), 127297. doi:10.1016/j.molstruc.2019.127297
• [49] Genc Bilgicli, H., Taslimi, P., Akyuz, B., Tuzun, B., & Gulcin, İ. Synthesis, characterization, biological evaluation, and molecular docking studies of some piperonyl‐based 4‐thiazolidinone derivatives. Archiv Der Pharmazie, (2019) e1900304. doi:10.1002/ardp.201900304
• [50] Roskoski, R. Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharmacological Research. 139 (2019) 395–411. doi:10.1016/j.phrs.2018.11.014.
• [51] Eckelman, B. P., Drag, M., Snipas, S. J., & Salvesen, G. S. The mechanism of peptide-binding specificity of IAP BIR domains. Cell Death & Differentiation, 15(5) (2008) 920–928. doi:10.1038/cdd.2008.6
• [52] Ma, O., Cai, W.-W., Zender, L., Dayaram, T., Shen, J., Herron, A. J., … Donehower, L. A. MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), Amplified on Chromosome 9, Collaborate with p53 Deficiency in Mouse Osteosarcoma Progression. Cancer Research, 69(6) (2009) 2559–2567. doi:10.1158/0008-5472.can-08-2929
• [53] Jung, S. A., Park, Y.-M., Hong, S.-W., Moon, J.-H., Shin, J.-S., Lee, H.-R., Kim, T. Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) Stability Contributes to YM155 Resistance in Human Gastric Cancer Cells. Journal of Biological Chemistry, 290(16) (2015) 9974–9985. doi:10.1074/jbc.m114.600874
• [54] Yang, C., Wang, H., Zhang, B., Chen, Y., Zhang, Y., Sun, X., Qin, S. LCL161 increases paclitaxel-induced apoptosis by degrading cIAP1 and cIAP2 in NSCLC. Journal of Experimental & Clinical Cancer Research, 35(1) (2016). doi:10.1186/s13046-016-0435-7
• [55] Cartier, J., Berthelet, J., Marivin, A., Gemble, S., Edmond, V., Plenchette, S., Dubrez, L. Cellular Inhibitor of Apoptosis Protein-1 (cIAP1) Can Regulate E2F1 Transcription Factor-mediated Control of Cyclin Transcription. Journal of Biological Chemistry, 286(30) (2011) 26406–26417. doi:10.1074/jbc.m110.191239.