Mathematical Modeling of the Biological Activity of a New Complex Compound Based on Palladium and Mexidol
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Burak Tüzün* Department of Plant and Animal Production, Technical Sciences Vocational School of Sivas, Sivas Cumhuriyet University, Sivas, Turkey.
Rana Jafarova, Ismail Bagirov, Nigar Magerramova, Tohfa Nasibova Department of Toxicology, Scientific Research Center, Azerbaijan Medical University, Baku, Azerbaijan.
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*E-mail: [email protected]
Abstract
Platinum preparations are widely used in the treatment of cancer patients, as they have an antitumor effect. However, the use of such drugs is limited due to their high toxicity. In this study, the goal was to reveal the anticancer activity of a new complex synthesized compound based on palladium and mexidol (2-ethyl-6-methyl-3-hydroxypyridine ammonium tetrachloropalladic acid), which has low toxicity. The interaction of palladium metal complexes with EGFR kinase protein (PDB ID: 2ITO) and their activity against these proteins were investigated. First, the palladium metal complex and protein have interacted with the HEX program. Afterward, PLIP analysis was performed to examine the interaction of metal complexes with protein in detail. Afterward, a Swiss ADME/T analysis of this palladium complex was performed. According to the Hodge and Sterner toxicity scale, the studied compound belongs to the group of moderately toxic substances that are allowed in medicine. As a result of the conducted calculations, the authors commented on the activity of the Pd metal complex. The interaction of the pd metal complex with the EFGR kinase protein was examined by PLIP analysis and its movements in human metabolism were predicted by ADME analysis of the Pd metal complex.
Keywords: Molecular docking, ADME/T, Anticancer effect, Palladium metal complex
Introduction
The search for new biologically active compounds for use in medical practice remains an important task of medical and pharmaceutical science (Taher et al., 2022; Nakagawa et al., 2021). Platinum preparations, widely used in the treatment of cancer patients, have shown a significant antitumor effect and prevent the development of metastases. However, their high toxicity limits their use. Thus, the search for new drugs with a similar effect, but less toxic, is carried out among the complex compounds of palladium, a metal from the platinum chemical group. Special attention is paid to structural analogs of cisplatin, as well as palladium compounds with pyridine derivatives (Tanaka et al., 2013; Kapdi & Fairlamb, 2014). At present, preparations based on palladium, such as morphosine and others, are recommended for oncological practice.
The search for effective but low-toxic chemotherapeutic agents among metal complexes similar in structure to platinum preparations, in which palladium is the complexing metal, is relevant due to the lower toxicity and equal efficiency of such compounds. A new complex compound based on palladium (Pd(II) and mexidol (ethylmethylhydroxypyridine succinate) was synthesized in the laboratory of the Azerbaijan Medical University, and its physicochemical properties were studied. It was found that the compound has the formula 2-ethyl-6-methyl-3-hydroxypyridine ammonium tetrachloropalladic acid and contains 2-valent palladium, coordinated with the organic core (Anvar & Magerramova, 2019; Jafarova & Magerramova, 2022). Studies also revealed that this compound has low toxicity. LD50 for male rats was 430 mg/kg and for white male mice – 355 mg/kg. According to the Hodge and Sterner toxicity scale (1943), it belongs to the group of moderately toxic substances. According to the GOST 12.1.007-76 toxicity classification of chemicals, it qualifies as a compound of the 3rd hazard class allowed for use in medicine (Anvar & Magerramova, 2019). The compound also has a pronounced radioprotective property (Jafarova & Magerramova, 2022).
The purpose of these studies was to identify the anticancer activity of the compound based on a mathematical model.
Materials and Methods
Recent studies showed that theoretical calculations have become an important method used in many processes such as how synthesis takes place and the characterization of molecules and comparison of the activities of molecules (Erdogan et al., 2023; Sarkı et al., 2023). Many programs can be used for these processes. However, it is one of many important programs used to examine the activities against EGFR kinase protein (Yun et al., 2007) using the HEX program (Ritchie & Orpailleur, 2013). Afterward, PLIP analysis (Adasme et al., 2021) was performed to examine in detail the interaction between the palladium complex and the protein. ADME/T analysis was then performed using SwissADME (Daina et al., 2017) to predict the effects and responses of the metal complex in human metabolism.
The biological activities of the complex against cancer proteins were compared. The proteins and metal complexes were studied at HEX 8.0.0 programs. The antibacterial calculations against the crystal structures were performed. The following parameters are used for docking: correlation type shape only, FFT mode: 3D, grid dimension: 0.6, receptor range: 180, ligand range: 180, twist range: 360, distance range: 40. Finally, the Protein-Ligand Interaction Profiler (PLIP) server confirmed the interaction between protein and the metal complex. Afterward, SwissADME was then made for ADME/T analysis of this palladium complex.
Results and Discussion
The most important thing is to compare their activities against biological materials. It is possible to compare the activities of metal complexes with the molecular docking calculations made for this purpose (Chalkha et al., 2023; Daoui et al., 2023). In calculations made to compare the activities of molecules and their metal complexes, the most important factor determining the activity of molecules and their metal complexes is the chemical interactions between molecules and proteins, which are hydrogen bonds, polar and hydrophobic interactions, π-π and halogen (Shahzadi et al., 2022; Rezaeivala et al., 2023). As these interactions increase, it is seen that the activities of the molecules and their metal complexes increase. It was observed that as the interactions of the molecules increased, the activity of the molecules increased because it inhibited the protein more (Alaysuy et al., 2022; Tapera et al., 2022). Among the parameters obtained in the calculations, the Etotal energy value shows the activity of molecules and their metal complexes. Etotal energy values of studied metal complexes are presented in Table 1.
Table 1. E total energy value of complex
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Pd metal complex |
-352.75 |
The interactions of the pd metal complex with the EGFR kinase protein are given in Figure 1.
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a) |
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b) |
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c) |
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Figure 1. Presentation interactions of Pd metal complex with EGFR kinase protein |
Chemical interactions between the pd metal complex and EGFR kinase protein were only Hydrophobic Interactions. between which atom and protein these interactions occur is presented in Table 2.
Table 2. Hydrophobic Interactions between Pd metal complex and EGFR kinase protein
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Index |
Residue |
AA |
Distance |
Ligand atom |
Protein atom |
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1 |
728A |
LYS |
3.17 |
3005 |
313 |
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2 |
730A |
LEU |
3.76 |
3021 |
332 |
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3 |
741A |
PRO |
3.76 |
3018 |
439 |
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4 |
794A |
PRO |
3.80 |
3025 |
928 |
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5 |
846A |
LYS |
3.92 |
3011 |
1460 |
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6 |
846A |
LYS |
3.76 |
3036 |
1459 |
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7 |
1012A |
ASP |
2.84 |
3029 |
2862 |
PLIP analysis was performed to examine further interactions in more detail. The numerical values of the interactions between the Pd metal complex and the proteins were obtained in Figure 2.
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Figure 2. Presentation interactions of Pd metal complex with EGFR kinase protein in PLİP |
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Figure 3. Drug likeness parameters of Pd metal complex |
It is given as the value of the Log P o/w of the molecules as the partition coefficient factor between octane and water solvents through the pharmacokinetic route, which is the classical indicator of lipophilicity (Alkandahri et al., 2021; Yusuf et al., 2021). Apart from these, it is very important to examine the behavior of the studied metal complexes against certain pharmacokinetic proteins such as P-glycoprotein (P-gp) and cytochromes P450 (CYP) (Tapera et al., 2022). It should be well known that the most important task of P-gp is to keep the central nervous system away from xenobiotics, on the other hand, this protein is secreted in some tumor cells and leads to drug-resistant cancers (Ukibayev et al., 2021; Lalthanpuii et al., 2022). It is also pharmacologically very important to understand how these compounds interact with cytochrome P450 (CYP) (Alaysuy et al., 2022; Bakchi et al., 2022). This group of iso-enzymes metabolically plays an important role in drug clearance, it has been suggested that CYP and P-gp may work together to metabolize small compounds synergistically to promote tissue and organism protection (AlRuwaili et al., 2022).
Table 3. ADME properties of metal complex
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Physicochemical Properties |
Druglikeness |
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Formula |
C16H22Cl4N2O2Pd |
Lipinski |
Yes; 1 violation: MW>500 |
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Molecular weight |
522.59 g/mol |
Ghose |
No; 1 violation: MW>480 |
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Num. heavy atoms |
25 |
Veber |
Yes |
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Num. arom. heavy atoms |
12 |
Egan |
Yes |
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Fraction Csp3 |
0.38 |
Muegge |
No; 1 violation: XLOGP3>5 |
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Num. rotatable bonds |
6 |
Bioavailability Score |
0.55 |
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Num. H-bond acceptors |
2 |
Water Solubility |
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Num. H-bond donors |
2 |
Log S (ESOL) |
-7.73 |
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Molar Refractivity |
105.27 |
Solubility |
9.86 10-06 mg/ml; 1.88 10-08 mol/l |
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TPSA |
48.22 Ų |
Class |
Poorly soluble |
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Lipophilicity |
Log S (Ali) |
-8.28 |
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Log Po/w (iLOGP) |
0.00 |
Solubility |
2.72 10-06 mg/ml; 5.20 10-09 mol/l |
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Log Po/w (XLOGP3) |
7.44 |
Class |
Poorly soluble |
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Log Po/w (WLOGP) |
4.48 |
Log S (SILICOS-IT) |
-6.38 |
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Log Po/w (MLOGP) |
2.81 |
Solubility |
2.20 10-04 mg/ml; 4.21 10-07 mol/l |
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Log Po/w (SILICOS-IT) |
3.46 |
Class |
Poorly soluble |
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Consensus LogPo/w |
3.64 |
Medicinal Chemistry |
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Pharmacokinetics |
PAINS |
0 alert |
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GI absorption |
High |
Brenk |
0 alert |
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BBB permeant |
Yes |
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P-gp substrate |
No |
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CYP1A2 inhibitor |
Yes |
Leadlikeness |
No; 2 violations: MW>350, XLOGP3>3.5 |
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CYP2C19 inhibitor |
No |
Synthetic accessibility |
3.31 |
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CYP2C9 inhibitor |
No |
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CYP2D6 inhibitor |
Yes |
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CYP3A4 inhibitor |
No |
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Log Kp (skin permeation) |
-4.21 cm/s |
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Conclusion
As a result of the theoretical calculations made, it was tried to comment on the activity of the Pd metal complex. The interaction of the pd metal complex with the EFGR kinase protein was examined by PLIP analysis. However, its movements in human metabolism were predicted by ADME analysis of the Pd metal complex.
Acknowledgments: None
Conflict of interest: None
Financial support: The numerical calculations reported in this paper were fully/partially performed at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources).
Ethics statement: The study was conducted in accordance with international ethical standards.
Adasme, M. F., Linnemann, K. L., Bolz, S. N., Kaiser, F., Salentin, S., Haupt, V. J., & Schroeder, M. (2021). PLIP 2021: Expanding the scope of the protein–ligand interaction profiler to DNA and RNA. Nucleic Acids Research, 49(W1), W530-W534.
Alaysuy, O., Abumelha, H. M., Alsoliemy, A., Alharbi, A., Alatawi, N. M., Osman, H. E., Zaky, R., & El-Metwaly, N. M. (2022). Elucidating of new hydrazide-based complexes derived from Pd (II), Cu (II) and Cd (II) ions: studies concerning spectral, DFT, Hirshfeld-crystal, biological screening beside Swiss-ADME verification. Journal of Molecular Structure, 1259, 132748.
Alkandahri, M. Y., Patala, R., Berbudi, A., & Subarnas, A. (2021). Antimalarial activity of curcumin and kaempferol using structure-based drug design method. Journal of Advanced Pharmacy Education & Research, 11(4), 87-90.
AlRuwaili, N. S. Q., Mohammad, A. A. T., Alnathir, H. F. S., Alfeheid, M. H. S., & Alshammari, N. N. Z. (2022). Illıcıt Drugs Addıctıon Among Patıents Wıth Chronıc Dıseases: Sımple Revıew Artıcle. Pharmacophore, 13(3), 81-85.
Anvar, J. R., & Magerramova, N. F. (2019). Study of acute and subchronic toxicity with determination of the cumuladia index for a metal-complex compound based on palladium and mexidol. Process Management and Scientific Developments, 113-117.
Bakchi, B., Krishna, A. D., Sreecharan, E., Ganesh, V. B. J., Niharika, M., Maharshi, S., Puttagunta, S. B., Sigalapalli, D. K., Bhandare, R. R., & Shaik, A. B. (2022). An overview on applications of SwissADME web tool in the design and development of anticancer, antitubercular and antimicrobial agents: A medicinal chemist's perspective. Journal of Molecular Structure, 132712.
Chalkha, M., El Hassani, A. A., Nakkabi, A., Tüzün, B., Bakhouch, M., Benjelloun, A. T., Sfaira, M., Saadi, M., El Ammari, L., & El Yazidi, M. (2023). Crystal structure, Hirshfeld surface and DFT computations, along with molecular docking investigations of a new pyrazole as a tyrosine kinase inhibitor. Journal of Molecular Structure, 1273, 134255.
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(1), 42717.
Daoui, S., Direkel, Ş., Ibrahim, M. M., Tüzün, B., Chelfi, T., Al-Ghorbani, M., Bouatia, M., Karbane, M. E., Doukkali, A., Benchat, N., et al. (2023). Synthesis, Spectroscopic Characterization, Antibacterial Activity, and Computational Studies of Novel Pyridazinone Derivatives. Molecules, 28(2), 678.
Erdogan, M. K., Gundogdu, R., Yapar, Y., Gecibesler, I. H., Kirici, M., Behcet, L., Tüzün, B., Taskin-Tok, T., & Taslimi, P. (2023). In vitro anticancer, antioxidant and enzyme inhibitory potentials of endemic Cephalaria elazigensis var. purpurea with in silico studies. Journal of Biomolecular Structure and Dynamics, 1-13.
Jafarova, R. E., & Magerramova, N. F. (2022). Evaluation of the effect of a complex compound based on palladium and mexidol on blood parameters in animals against the background of X-ray irradiation. Bulletin of the Smolensk State Medical Academy, 3, 33-41.
Kapdi, A. R., & Fairlamb, I. J. (2014). Anti-cancer palladium complexes: a focus on PdX₂L₂, palladacycles and related complexes. Chemical Society Reviews, 43(13), 4751-4777.
Lalthanpuii, K., Kaur, J., Saini, S., Bhatti, K., & Nain, P. (2022). Strengthen the Monitoring and Reporting of Adverse Drug Reaction at a Tertiary Teaching Hospital. Archives of Pharmacy Practice, 13(1), 61-67.
Nakagawa, N., Odanaka, K., Ohara, H., & Kisara, S. (2021). Evaluation of drug information literacy gained through e-learning to prepare students for practical pharmacy experience. Journal of Advanced Pharmacy Education & Research, 11(4), 111-115.
Rezaeivala, M., Bozorg, M., Rafiee, N., Sayin, K., & Tuzun, B. (2023). Corrosion inhibition of Carbon Steel using a new morpholine-based ligand during acid pickling: Experimental and theoretical studies. Inorganic Chemistry Communications, 148, 110323.
Ritchie, D., & Orpailleur, T. (2013). Hex 8.0. 0 User Manual. Protein Docking Using Spherical Polar Fourier Correlations Copyright c.
Sarkı, G., Tüzün, B., Ünlüer, D., & Kantekin, H. (2023). Synthesis, characterization, chemical and biological activities of 4-(4-methoxyphenethyl)-5-benzyl-2-hydroxy-2H-1, 2, 4-triazole-3 (4H)-one phthalocyanine derivatives. Inorganica Chimica Acta, 545, 121113.
Shahzadi, I., Zahoor, A. F., Tüzün, B., Mansha, A., Anjum, M. N., Rasul, A., Irfan, A., Kotwica-Mojzych, K., & Mojzych, M. (2022). Repositioning of acefylline as anti-cancer drug: Synthesis, anticancer and computational studies of azomethines derived from acefylline tethered 4-amino-3-mercapto-1, 2, 4-triazole. Plos one, 17(12), e0278027.
Taher, S. S., Al-Kinani, K. K., Hammoudi, Z. M., & Mohammed Ghareeb, M. (2022). Co-surfactant effect of polyethylene glycol 400 on microemulsion using BCS class II model drug. Journal of Advanced Pharmacy Education & Research, 12(1), 63-69.
Tanaka, M., Kataoka, H., Yano, S., Ohi, H., Kawamoto, K., Shibahara, T., Mizoshita, T., Mori, Y., Tanida, S., Kamiya, T. et al. (2013). Anti-cancer effects of newly developed chemotherapeutic agent, glycoconjugated palladium (II) complex, against cisplatin-resistant gastric cancer cells. BMC Cancer, 13, 1-9. doi:10.1186/1471-2407-13-237
Tapera, M., Kekeçmuhammed, H., Tüzün, B., Sarıpınar, E., Koçyiğit, Ü. M., Yıldırım, E., Doğan, M., & Zorlu, Y. (2022). Synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular docking studies of new imidazolyl hydrazone derivatives. Journal of Molecular Structure, 1269, 133816.
Ukibayev, J., Datkhayev, U., Myrzakozha, D., Frantsev, A., Karlova, E., Nechepurenko, Y., Balpanova, D., & Almabekova, A. (2021). Rectal methods of delivery of medical drugs with a protein nature in the therapies of tumor disease. Journal of Advanced Pharmacy Education & Research, 11(1), 18-22.
Yun, C. H., Boggon, T. J., Li, Y., Woo, M. S., Greulich, H., Meyerson, M., & Eck, M. J. (2007). Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell, 11(3), 217-227.
Yusuf, N. A., Abdassah, M., Mauludin, R., Joni, I. M., & Yohana, A. (2021). Transfersome: a vesicular drug delivery with enhanced permeation. Journal of Advanced Pharmacy Education & Research, 11(3), 48-57.
