Steroidal konjugatların in vitro biyolojik aktivite ve in silico moleküler bağlanma çalışmaları

Yıl 2024, , 10 - 19, 30.06.2024

Sevinç İlkar Erdağı

https://doi.org/10.46239/ejbcs.1418794

Öz

Steroidal bileşikler, hormon reseptörleri ve steroidojenik enzimler için ligandlar veya substratlar olarak görev yaparlar. Bu bileşikler, hücre büyümesi ve çoğalma gibi birçok biyolojik süreçte etkili rol oynarlar. Daha önce yapılan çalışmalar steroid bileşiklerinin kanser hücrelerini hedefleme ve kanser tedavisinde kullanma potansiyelini göstermektedir. Steroid bileşiklerinin biyolojik olarak aktif 4-metil-7-hidroksi kumarin bileşiği ile konjuge edilerek yeni konjugatlar geliştirildiği daha önceki çalışmada bildirildi. Bu çalışmada ise, steroidal konjugatların hormona duyarlı ve diğer kanser hücre hatları üzerinde farmakolojik özellikleri incelendi ve in vitro olarak değerlendirildi. Seçicilik indeksinin belirlenmesi amacıyla sağlıklı hücre hattına karşı proliferasyonları in vitro olarak test edildi. Ayrıca, bu çalışmada ilk olarak, etkin konjugatlar üzerinde protein-ligand etkileşimleri, bağlanma ilgilerini belirlemek amacıyla in silico moleküler bağlanma çalışmaları yapıldı. Bu çalışmanın sonuçları, steroid temelli konjugatların çeşitli hastalıkların tedavisine çok yönlü bir yaklaşım sunma potansiyeline sahip olduğunu göstermektedir.

Anahtar Kelimeler

Antiproliferatif aktivite, Biyokonjugat, 4-metil-7-hidroksi kumarin, Moleküler bağlanma, Steroid

In vitro biological activity and in silico molecular binding studies of steroidal conjugates

Öz

Steroidal compounds effectively participate in various biological activities, including cellular growth and proliferation, by functioning as ligands or substrates for hormone receptors and steroidogenic enzymes. Previous studies have shown the potential of steroid conjugates in targeting cancer cells and their use in cancer treatment. The previous study reported that new conjugates were developed by conjugating steroid compounds with the biologically active 4-methyl-7-hydroxycoumarin compound. In this study, the pharmacological properties of steroidal conjugates were examined and evaluated in vitro on hormone-sensitive and other cancer cell lines. The proliferation against a healthy cell line was tested in vitro to determine the selectivity index. Additionally, in silico molecular docking studies were conducted for the first time in this study to determine the binding affinities of effective conjugates. The results of this study demonstrate that steroid-based conjugates have the potential to offer a versatile approach to the treatment of various diseases.

Anahtar Kelimeler

Antiproliferative activity, Bioconjugate, 4-methyl-7-hydroxy coumarin, Molecular docking, Steroid.

Kaynakça

• Bansal R, Suryan A. 2022. A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery. ACS Bio & Med Chem Au. 2(4): 340–369.
• Cai B, Liao A, Lee K K, Ban J S, Yang, H S, Im Y J, Chun C. 2016. Design, synthesis of methotrexate-diosgenin conjugates and biological evaluation of their effect on methotrexate transport-resistant cells. Steroids. 116: 45–51.
• Cai D, Qi J, Yang Y, Zhang W, Zhou F, Jia X, Guo W, Huang X, Gao F, Chen H, Li T, Li G, Wang P, Zhang Y, Lei H. 2019. Design, Synthesis and Biological Evaluation of Diosgenin-Amino Acid Derivatives with Dual Functions of Neuroprotection and Angiogenesis. Molecules. 24(22): 4025.
• Cortes J, Simeon T, Ruiz de Angulo V, Guieysse D, Remaud-Simeon M, Tran V. 2005. A path planning approach for computing large-amplitude motions of flexible molecules. Bioinformatics. 21(1): 116–125.
• Dembitsky V M, Gloriozova T A, Imbs A B. 2018. Ferrocene and titanocene steroid conjugates: Structures and activities a brief review. Vietnam J Chem. 56(2): 127–138.
• DeVore N M, Scott E E. 2012. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature. 482(7383): 116–119.
• Eberhardt J, Santos-Martins D, Tillack A F, Forli S. 2021. AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. J Chem Inf Model. 61(8): 3891–3898.
• Ghosh D, Griswold J, Erman M, Pangborn W. 2009. Structural basis for androgen specificity and estrogen synthesis in human aromatase. Nature. 457(7226): 219–223.
• Hani U, Osmani R A M, Bhosale R R, Shivakumar H G, Kulkarni P K. 2016. Current Perspectives on Novel Drug Delivery Systems and Approaches for Management of Cervical Cancer: A Comprehensive Review. Curr Drug Targets. 17(3): 337–352.
• Ilkar Erdagi S. 2023. Steroid‐Hymecromone Conjugates with Improved Antiproliferative and Antimicrobial Potential: Synthesis, Biological Evaluation, and in silico ADME Prediction. ChemistrySelect. 8(25).
• Ilkar Erdagi S, Uyanik C. 2019. Biological evaluation of bioavailable amphiphilic polymeric conjugate based on natural products: diosgenin and curcumin. Int J Poly Mater. 69(2): 73–84.
• Ilkar Erdagi S, Yildiz U. 2022. Synthesis of diosgenin derivatives by A and B ring modifications and low-valent titanium (Ti0)-catalyzed McMurry coupling reactions and designing to create novel biological agents. J Mol Struct. 1256: 132511.
• Ke S, Shi L, Yang Z. 2015. Discovery of novel isatin–dehydroepiandrosterone conjugates as potential anticancer agents. Bioorganic Med. Chem. Lett. 25(20): 4628–4631.
• Kowalczyk W, Waliszczak G, Jach R, Dulinska-Litewka J. 2021. Steroid Receptors in Breast Cancer: Understanding of Molecular Function as a Basis for Effective Therapy Development. Cancers. 13(19): 4779.
• Kurmi B D, Paliwal R, Paliwal S R. 2020. Dual cancer targeting using estrogen functionalized chitosan nanoparticles loaded with doxorubicin-estrone conjugate: A quality by design approach. Int J Biol Macromol.164: 2881–2894.
• Mahalakshmi N, Parthasarathy M. 2023. Growth, structural, spectroscopic, DFT calculations, insilico biological analysis of glycine methyl ester hydrochloride (GMEHCl) against human estrogen receptor. Chem Phys Impact.7: 100303.
• Matsuzaki Y, Honda A. 2006. Dehydroepiandrosterone and Its Derivatives: Potentially Novel Anti-Proliferative and Chemopreventive Agents. Curr Pharm Des. 12(26): 3411–3421.
• Michalak M, Lach M S, Antoszczak M, Huczynski A, Suchorska W M. 2020. Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives-An In Vitro Study. Molecules. 25(3): 537.
• Navacchia M L, Marchesi E, Perrone D. 2020. Bile Acid Conjugates with Anticancer Activity: Most Recent Research. Molecules. 26(1): 25.
• Nikolic A R, Petri E T, Klisuric O R, Celic A S, Jakimov D S, Djurendic E A, Penov Gasi K M, Sakac M N. 2015. Synthesis and anticancer cell potential of steroidal 16,17-seco-16,17a-dinitriles: Identification of a selective inhibitor of hormone-independent breast cancer cells. Bioorg Med Chem. 23(4): 703–711.
• Osuji I J, Vera-Bolanos E, Carmody T J, Brown E S. 2010. Pregnenolone for cognition and mood in dual diagnosis patients. Psychiatry Res. 178(2): 309–312.
• Pereira de Jesus‐Tran K, Cote P, Cantin L, Blanchet J, Labrie F, Breton R. 2006. Comparison of crystal structures of human androgen receptor ligand‐binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity. Protein Sci. 15(5): 987–999.
• Rocha-Roa C, Cortes E, Cuesta S A, Mora J R, Paz J L, Flores-Sumoza M, Marquez E A. 2023. Study of potential inhibition of the estrogen receptor α by cannabinoids using an in silico approach: Agonist vs antagonist mechanism. Comput Biol Med. 152: 106403.
• Savic M P, Skoric D, Kuzminac I Z, Jakimov D S, Kojic V V, Rarova L, Strnad M, Djurendic E A. 2020. New A-homo lactam D-homo lactone androstane derivative: Synthesis and evaluation of cytotoxic and anti-inflammatory activities in vitro. Steroids. 157: 108596.
• Shiau A K, Barstad D, Loria P M, Cheng L, Kushner P J, Agard D A, Greene G L. 1998. The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen. Cell. 95(7): 927–937.
• Sreenatha V, Srinivasa S M, Rajendra Prasad K. 2022. Design, synthesis, bioevaluation, DFT, docking, and molecular dynamic simulation for selected novel 1,3,4-Oxadiazole - indole derivatives hybrid against estrogen receptor alpha. J Mol Struct. 1269: 133789.
• Trott O, Olson A J. 2009. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31(2): 455–461.
• Trouillas P, Corbiere C, Liagre B, Duroux J L, Beneytout J L. 2005. Structure–function relationship for saponin effects on cell cycle arrest and apoptosis in the human 1547 osteosarcoma cells: a molecular modelling approach of natural molecules structurally close to diosgenin. Bioorg Med Chem. 13(4): 1141–1149.
• Xu L, Xu D, Li Z, Gao Y, Chen H. 2019. Synthesis and potent cytotoxic activity of a novel diosgenin derivative and its phytosomes against lung cancer cells. Beilstein J Nanotechnol. 10: 1933–1942.
• Xu Z, Zhang T, Prinyawiwatkul W, Samuel Godber J. 2005. Capabilities of different cooking oils in prevention of cholesterol oxidation during heating. J Am Oil Chem Soc. 82(4): 243–248.
• Yu K H, Lee T L M, Wang C S, Chen Y J, Re C, Kou S C, Chiang J H, Kohane I S, Snyder M. 2018. Systematic Protein Prioritization for Targeted Proteomics Studies through Literature Mining. J Proteome Res.17(4): 1383–1396.