Molecular Docking Analysis of Benzimidazolium Type Molecules with VEGFR-2 and TrxR Crystal Structures for Evaluating Anti-Cancer Activity

Year 2021, Volume: 11 Issue: 1, 36 - 44, 30.06.2021

Elvan Üstün , Neslihan Şahin

Abstract

N-heterocyclic carbenes are a family of molecules that are frequently studied for their bioactivity. Since cancer is the second disease that causes death in the world, the anti-cancer properties of N heterocyclic carbenes is one of the analyzed activities. Considering the difficulties of studying the bioactivities of all candidate molecules, using in-silico methods for obtaining predictions is advantageous. With theoretical ways, both the properties of the existed molecules can be examined, and preliminary information can be obtained for designing of more suitable molecules. In this study, previously characterized of 1-(allyl)-3-(2,4,6-trimethylbenzyl)benzimidazolium chloride (1) and 1-(allyl)-3-(2,3,4,5,6-pentamethylbenzyl)benzimidazolium chloride (2) have been optimized by DFT-based calculation methods. In addition, the interactions of optimized molecules with VEGFR-2 and TrxR crystal structures were analyzed by using molecular docking methods.

Keywords

N-Heterocyclic Carbenes, Anti-cancer, Molecular Docking, DFT

Benzimidazolyum Tipi Moleküllerin Anti-Kanser Aktivitesini Değerlendirmek İçin VEGFR-2 ve TrxR Kristal Yapılarıyla Moleküler Doking Analizi

Abstract

N-heterosiklik karbenler biyoaktiviteleri dolayısıyla sıklıkla incelenen bir molekül ailesidir. Kanserin dünyada ölüme neden olan 2. hastalık olduğu için, N-heterosiklik karbenlerin anti-kanser aktivitesi de incelenen özellikler arasındadır. Bütün aday moleküllerin biyoaktivitesinin incelenmesinin zorlukları değerlendirildiğinde, in-siliko yöntemlerin öngörü elde etmek için kullanılması avantajlıdır. Teorik hesaplama yöntemleriyle, mevcut moleküllerin özellikleri incelenebildiği gibi daha uygun moleküllerin sentezlenmesi için önbilgiler elde edilebilir. Bu çalışmada daha önce karakterize edilmiş 1-(allil)-3-(2,4,6-trimetilbenzil)benzimidazolyum klorür (1) ve 1-(allil)-3-(2,3,4,5,6-pentametilbenzil)benzimidazolyum klorür (2) molekülleri DFT temelli hesap yöntemleri ile yapısal olarak incelenerek optimize edilmiştir. Optimize moleküllerin VEGFR-2 ve TrxR kristal yapıları ile etkileşimleri moleküler doking yöntemleri kullanılarak analiz edilmiştir.

Keywords

N-Heterosiklik Karbenler, Anti-kanser, Moleküler Doking, DFT

References

• Arduengo AJ, Harlow RL & Kline M. (1991) A stable crystalline carbene. Journal American Chemical Society 113(1):361–363.
• Arnér ESJ & Holmgren A. (2006) The thioredoxin system in cancer. Seminars in Cancer Biology 16(6):420-426.
• Dawson MA & Kouzarides T. (2012) Cancer Epigenetics: From Mechanism to Therapy. Cell 150(1):12-27.
• Frémont P, Marion N & Nolan SP. (2009) Cationic NHC–gold(I) complexes: Synthesis, isolation, and catalytic activity. Journal of Organometallic Chemistry 694(4):551-560.
• Ganther HE. (1999) Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase. Carcinogenesis 20(9):1657–1666.
• Gupta GP & Massagué J. (2006) Cancer Metastasis: Building a Framework. Cell 127(4):679-695.
• Holt PA, Chaire JB & Trent JO. (2008) Molecular Docking of Intercalators and Groove-Binders to Nucleic Acids Using Autodock and Surflex. Journal of Chemical Information and Modeling 48(8):1602–1615.
• https://www.who.int/health-topics/cancer#tab=tab_1
• Kaya S, Banerjee P, Sah S,Tüzün B & Kaya C. (2016) Theoretical evaluation of some benzotriazole and phospono derivatives as aluminum corrosion inhibitors: DFT and molecular dynamics simulation approaches. RSC Advances 6:74550-74559.
• Lincoln DT, Emadi AEM, Tonissen KF & Clarke FM. (2003) The thioredoxin-thioredoxin reductase system: over-expression in human cancer. Anticancer Research 23(3B):2425-2433.
• Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, Jemal A, Kramer JL & Siegel RL. (2019) Cancer treatment and survivorship statistics. CA: A Cancer Journal for Clinicians 69(5):363-385.
• Miyazaki Y, Matsunaga S, Tang J, Maeda Y, Nakano M, Philippe R.J, Shibahara M, Liu W, Sato H, Wang L & Nolte RT. Novel 4-amino-furo[2,3-d]pyrimidines as Tie-2 and VEGFR2 dual inhibitors. Bioorganic Medical Chemical Letter 15:2203-2207.
• Mnasri A, Al-Ayed A.S. Özdemir İ, Gürbüz N, Naceur, H. (2021). A new PEPPSI type N-heterocyclic carbene palladium (II) complexes and its efficiency as a catalyst for Mizoroki-Heck cross-coupling reactions in water: Synthesis, Characterization and their antimicrobial and Cytotoxic activities. Journal of Molecular Structure, 1234: 130204.
• Morell C, Grand A & Toro-Labbé A. (2005) New Dual Descriptor for Chemical Reactivity Journal Physical Chemistry A 109(1):205–212.
• Nair V, Bindu S & Sreekumar V. (2004) N‐Heterocyclic Carbenes: Reagents, Not Just Ligands!. Angewandte Chemie International Edition 43(39):5130 –5135.
• Neese F, Wennmohs F, Becker U & Riplinger C. (2020) The ORCA quantum chemistry program package. Journal of Chemical Physics 152:224108.
• Neese F. (2006) Importance of Direct Spin−Spin Coupling and Spin-Flip Excitations for the Zero-Field Splittings of Transition Metal Complexes:  A Case Study. Journal American Chemical Society 128(31):10213–10222.
• Neese F. (2012) The ORCA program system. Wiley Interdisciplinary Reviews: Computational Molecular Science 2:73–78.
• Nguyen P, Awwad RT, Smart DDK, Spitz DR & Gius D. (2006) Thioredoxin reductase as a novel molecular target for cancer therapy. Cancer Letters 236(2):164-174.
• Nordling CO. (1953) A New Theory on the Cancer-inducing Mechanism. British Journal of Cancer 7(1):68-72.
• Parsonage D, Sheng F, Hirata K, Debnath A, Mckerrow JH, Reed SL, Abagyan R, Poole LB & Podust LM. X-Ray Structures of Thioredoxin and Thioredoxin Reductase from Entamoeba Histolytica and Prevailing Hypothesis of the Mechanism of Auranofin Action. Journal of Structural Biology 194:180.
• Parthasarathi R, Subramanian V, Roy DR & Chattaraj PK. (2004) Electrophilicity index as a possible descriptor of biological activity. Bioorganic & Medicinal Chemistry 12(21):5533-5543.
• Rapisard & Melillo G. (2012) Role of the VEGF/VEGFR Axis in Cancer Biology and Therapy. Advances in Cancer Research 114:237-267
• Şahin N, Bölükbaşı SŞ, Tahir MN, Arıcı C, Çevik E, Gürbüz N, Özdemir İ & Cummings BS. (2019) Synthesis, characterization and anticancer activity of allyl substituted N-Heterocyclic carbene silver(I) complexes. Journal of Molecular Structure 1179:92-99.
• Serdaroğlu G & Şahin N. (2019) The synthesis and characterization of 1-(Allyl)-3-(2-methylbenzyl)benzimidazolium chloride: FT-IR, NMR, and DFT computational investigation. Journal of Molecular Structure 1178:212-221.
• Serdaroğlu G, Uludağ N, Ercag E, Suguma P & Rajkumar P. (2021) Carbazole derivatives: Synthesis, spectroscopic characterization, antioxidant activity, molecular docking study, and the quantum chemical calculations. Journal of Molecular Liquids 330:115651.
• Sitohy B, Nagy JA & Dvorak HF. (2012) Anti-VEGF/VEGFR Therapy for Cancer: Reassessing the Target. Cancer Research 72(8):1909–1914.
• Spannuth WA, Nick AM, Jennings NB, Armaiz‐Pena GN, Mangala LS, Danes CG, Lin YG, Merritt WM, Thaker PH, Kamat AA, Han LY, Tonra JR, Coleman RL, Ellis LM & Sood AK. (2009) Functional significance of VEGFR‐2 on ovarian cancer cells. International Journal of Cancer 124(5):1045-1053.
• Tanno S, Ohsaki Y, Nakanishi K, Toyoshima E & Kikuchi K. (2004) Human small cell lung cancer cells express functional VEGF receptors, VEGFR-2 and VEGFR-3. Lung Cancer 46(1):11-19
• Trott O & Olson AJ. (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.
• Viciu MS, Kelly RA, Stevens ED, Naud F, Studer M & Nolan SP. (2003) Synthesis, Characterization, and Catalytic Activity of N-Heterocyclic Carbene (NHC) Palladacycle Complexes. Organic Letters 5(9):1479–1482.
• Vijayaraj R, Subramanian V & Chattaraj PK. (2009) Comparison of Global Reactivity Descriptors Calculated Using Various Density Fun ctionals: A QSAR Perspective. Journal of Chemical Theory and Computation 5(10):2744–2753
• Waks AG & Winer EP. (2019) Breast Cancer Treatment. JAMA 321(3):288-300.