A Prominent Candidate in Natural Product Discovery for Multi-Target Cancer Therapy: Structure-Based Assessment of Hyperforin

Yıl 2025, Cilt: 11 Sayı: 2, 75 - 95, 25.12.2025

Gülşah Aydın

Öz

In this study, the binding affinities of nine key phytochemical compounds found in the flora of Turkey on the targets Kirsten rat sarcoma viral oncogene homolog (KRAS), Mouse double minute 2 homolog (MDM2), WEE1 G2 checkpoint kinase (WEE1), fibroblast growth factor receptor 4 (FGFR4), and Poly(ADP-ribose) polymerase 1 (PARP1) were comparatively investigated using a structure-based approach. This aimed to uncover natural molecular scaffolds that could simultaneously affect critical axes of tumor progression such as cell proliferation, DNA damage response, and mitotic control. GA-based docking studies were performed on the target structures obtained from the PDB using AutoDock. Binding modes were selected using RMSD clustering, and interaction profiles were examined in detail in 2D and 3D. The results showed that hyperforin stood out by exhibiting the strongest multiple binding performance on the targets KRAS (–8.04 kcal/mol), MDM2 (–9.15 kcal/mol), and WEE1 (–8.29 kcal/mol). Significant affinity for FGFR4 was observed only for hyperforin. Docking results for PARP1 revealed that the investigated compounds did not significantly overlap with the catalytic site. Acetylchiconine, tiliroside, and berberine were considered rational seed cells for derivative development because they offered moderate-to-high binding potential on KRAS and WEE1. Overall, the consistent and strong binding profile of hyperforin along the KRAS–MDM2–WEE1 axis suggests a multilayered suppression strategy that allows simultaneous targeting of three key oncobiological mechanisms: suppression of proliferative signaling, reactivation of the p53-mediated DNA damage response, and control of the G2/M transition. This suggests that the molecule may be a high-potential candidate for preclinical validation.

Anahtar Kelimeler

KRAS , MDM2 , WEE1 , Cancer , Hyperforin

Etik Beyan

There are no ethical issues with the publication of this article.

Çok Hedefli Kanser Tedavisi için Doğal Ürün Keşfinde Öne Çıkan Bir Aday: Hiperforinin Yapıya Dayalı Değerlendirmesi

Öz

Bu çalışmada, Türkiye florasında yaygın bulunan dokuz temel fitokimyasal bileşiğin KRAS (Kirsten rat sarcoma viral oncogene homolog), MDM2 (Mouse double minute 2 homolog), WEE1 (WEE1 G2 checkpoint kinase), FGFR4 (fibroblast growth factor receptor 4) ve PARP1 (Poly(ADP-ribose) polymerase 1) hedefleri üzerindeki bağlanma eğilimleri yapı-temelli yaklaşımla karşılaştırmalı olarak incelendi. Böylece hücre proliferasyonu, DNA hasar yanıtı ve mitotik kontrol gibi tümör progresyonunun kritik eksenlerini aynı anda etkileyebilecek doğal moleküler iskeletlerin ortaya çıkarılması amaçlandı. PDB’den elde edilen hedef yapılar üzerinde AutoDock ile GA-tabanlı yerleştirme çalışmaları gerçekleştirildi ve bağlanma modları RMSD-kümeleme ile seçilerek etkileşim profilleri 2-boyutlu ve 3-boyutlu olarak ayrıntılı incelendi. Elde edilen sonuçlar hiperforinin; KRAS (–8.04 kcal/mol), MDM2 (–9.15 kcal/mol) ve WEE1 (–8.29 kcal/mol) hedeflerinde en güçlü çoklu bağlanma performansını sergileyerek açık ara öne çıktığını gösterdi. FGFR4 için anlamlı afinite yalnızca hiperforinde gözlendi. PARP1 için elde edilen yerleştirme sonuçları, incelenen bileşiklerin katalitik bölgeyle anlamlı bir şekilde örtüşmediğini ortaya koydu. Asetilşikonin, tilirosid ve berberin; KRAS ve WEE1 üzerinde orta-yüksek düzeyde bağlanma potansiyeli sunduğu için türev geliştirme açısından rasyonel çekirdekler olarak değerlendirildi. Genel olarak, hiperforinin KRAS–MDM2–WEE1 ekseni boyunca tutarlı ve güçlü bağlanma profili, proliferatif sinyallemenin baskılanması, p53 aracılı DNA hasar yanıtının yeniden etkinleştirilmesi ve G2/M geçişinin kontrol altına alınması gibi üç temel onkobiyolojik mekanizmanın eşzamanlı olarak hedeflenmesine olanak tanıyan çok katmanlı bir baskılama stratejisine işaret etmekte olup, molekülün klinik öncesi doğrulamalar için yüksek potansiyele sahip bir aday olabileceğini gösterdi.

Anahtar Kelimeler

KRAS , MDM2 , WEE1 , Kanser , Hiperforin

Etik Beyan

Bu makalenin yayınlanmasında etik açıdan herhangi bir sorun bulunmamaktadır.

Kaynakça

• Emre, G., Dogan, A., Haznedaroglu, M. Z., Senkardes, I., Ulger, M., Satiroglu, A., Can Emmez, B., & Tugay, O. (2021). An ethnobotanical study of medicinal plants in Mersin (Turkey). Frontiers in pharmacology, 12, 664500.
• Newman, D. J., & Cragg, G. M. (2020). Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. Journal of Natural Products, 83(3), 770-803.
• Yip, H. Y. K., & Papa, A. (2021). Signaling pathways in cancer: therapeutic targets, combinatorial treatments, and new developments. Cells, 10(3), 659.
• Wei, H., & McCammon, J. A. (2024). Structure and dynamics in drug discovery. npj Drug Discovery, 1(1), 1.
• Batool, M., Ahmad, B., & Choi, S. (2019). A structure-based drug discovery paradigm. International journal of molecular sciences, 20(11), 2783.
• Curtin, N. J., & Szabo, C. (2013). Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Molecular aspects of medicine, 34(6), 1217-1256.
• Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., & O'Connor, M. J. (2009). Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. New England Journal of Medicine, 361(2), 123-134.
• Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013). K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 503(7477), 548-551.
• Lanman, B. A., Allen, J. R., Allen, J. G., Amegadzie, A. K., Ashton, K. S., Booker, S. K., Chen, J. J., Chen, N., Frohn, M. J., & Goodman, G. (2019). Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors. In: ACS Publications.
• Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., & Koppada, N. (2019). The clinical KRAS (G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature, 575(7781), 217-223.
• Aydin, G., Paksoy, M. N., Orhan, M. D., Avsar, T., Yurtsever, M., & Durdagi, S. (2020). Proposing novel MDM2 inhibitors: Combined physics‐driven high‐throughput virtual screening and in vitro studies. Chemical Biology & Drug Design, 96(1), 684-700.
• Vass, M., Schmidt, É., Horti, F., & Keserű, G. M. (2014). Virtual fragment screening on GPCRs: a case study on dopamine D3 and histamine H4 receptors. European journal of medicinal chemistry, 77, 38-46.
• Erdoğan, Ü., Onem, E., Muhammed Tilahun, M., Soyocak, A., Ak, A., Arın, U. E., & Erzurumlu, Y. (2025). Investigation of Antioxidant, Antibacterial, and Anticancer Activities, and Molecular Modeling Studies of Berberis crataegina Fruit Extract. Chemistry & Biodiversity, e202402591.
• Zhao, Q. (2015). Molecular mechanisms of shikonin and its derivatives in cancer therapy Mainz, Univ., Diss.
• Menegazzi, M., Masiello, P., & Novelli, M. (2020). Anti-tumor activity of Hypericum perforatum L. and hyperforin through modulation of inflammatory signaling, ROS generation and proton dynamics. Antioxidants, 10(1), 18.
• Wen, C., Dechsupa, N., Yu, Z., Zhang, X., Liang, S., Lei, X., Xu, T., Gao, X., Hu, Q., & Innuan, P. (2023). Pentagalloyl glucose: a review of anticancer properties, molecular targets, mechanisms of action, pharmacokinetics, and safety profile. Molecules, 28(12), 4856.
• Rauf, A., Olatunde, A., Akram, Z., Hemeg, H. A., Aljohani, A. S., Al Abdulmonem, W., Khalid, A., Khalil, A. A., Islam, M. R., & Thiruvengadam, R. (2025). The role of pomegranate (Punica granatum) in cancer prevention and treatment: Modulating signaling pathways from inflammation to metastasis. Food Science & Nutrition, 13(2), e4674.
• Vyas, S., Kothari, S., & Kachhwaha, S. (2019). Nootropic medicinal plants: Therapeutic alternatives for Alzheimer’s disease. Journal of Herbal Medicine, 17, 100291.
• Yeşil, Y., & Akalın, E. (2009). Folk medicinal plants in Kürecik area (Akçadağ/Malatya Turkey). Turkish Journal of Pharmaceutical Sciences, 6(3), 207-220.
• Rahimi-Madiseh, M., Lorigoini, Z., Zamani-Gharaghoshi, H., & Rafieian-Kopaei, M. (2017). Berberis vulgaris: specifications and traditional uses. Iranian journal of basic medical sciences, 20(5), 569.
• Imenshahidi, M., & Hosseinzadeh, H. (2016). Berberis vulgaris and berberine: an update review. Phytotherapy research, 30(11), 1745-1764.
• Tillhon, M., Ortiz, L. M. G., Lombardi, P., & Scovassi, A. I. (2012). Berberine: new perspectives for old remedies. Biochemical Pharmacology, 84(10), 1260-1267.
• Damare, R., Engle, K., & Kumar, G. (2024). Targeting epidermal growth factor receptor and its downstream signaling pathways by natural products: A mechanistic insight. Phytotherapy research, 38(5), 2406-2447.
• Polat, R., Cakilcioglu, U., & Satıl, F. (2013). Traditional uses of medicinal plants in Solhan (Bingöl—Turkey). Journal of ethnopharmacology, 148(3), 951-963.
• Papageorgiou, V. P., Assimopoulou, A. N., Samanidou, V., & Papadoyannis, I. (2006). Recent advances in chemistry, biology and biotechnology of alkannins and shikonins. Current Organic Chemistry, 10(16), 2123-2142.
• Zhao, R., Choi, B. Y., Wei, L., Fredimoses, M., Yin, F., Fu, X., Chen, H., Liu, K., Kundu, J. K., & Dong, Z. (2020). Acetylshikonin suppressed growth of colorectal tumour tissue and cells by inhibiting the intracellular kinase, T‐lymphokine‐activated killer cell‐originated protein kinase. British journal of pharmacology, 177(10), 2303-2319.
• Uslusoy, F., Nazıroğlu, M., Övey, İ. S., & Sönmez, T. T. (2019). Hypericum perforatum L. supplementation protects sciatic nerve injury-induced apoptotic, inflammatory and oxidative damage to muscle, blood and brain in rats. Journal of pharmacy and pharmacology, 71(1), 83-92.
• Özkan, E. E., & Mat, A. (2013). An overview on Hypericum species of Turkey. Journal of Pharmacognosy and Phytotherapy, 5(3), 38-46.
• Cardile, A., Zanrè, V., Campagnari, R., Asson, F., Addo, S. S., Orlandi, E., & Menegazzi, M. (2023). Hyperforin elicits cytostatic/cytotoxic activity in human melanoma cell lines, inhibiting pro-survival NF-κB, STAT3, AP1 transcription factors and the expression of functional proteins involved in mitochondrial and cytosolic metabolism. International journal of molecular sciences, 24(2), 1263.
• Barathan, M., Zulpa, A. K., Vellasamy, K. M., Ibrahim, Z. A., Hoong, S. M., Mariappan, V., Venkatraman, G., & Vadivelu, J. (2023). Hyperforin-mediated anticancer mechanisms in MDA-MB-231 cell line: insights into apoptotic mediator modulation and caspase activation. Journal of Taibah University for Science, 17(1), 2237712.
• Tatli, I. I., & Akdemir, Z. F. (2006). Traditional uses and biological activities of Verbascum species. Fabad Journal of Pharmaceutical Sciences, 31(2), 85.
• Kahraman, C., Ekizoglu, M., Kart, D., Akdemir, Z., & Tatli, I. I. (2011). Antimicrobial activity of some Verbascum species growing in Turkey. Fabad Journal of Pharmaceutical Sciences, 36(1), 11-16.
• Ozcan, B., Yilmaz, M., & Caliskan, M. (2010). Antimicrobial and antioxidant activities of various extracts of Verbascum antiochium Boiss.(Scrophulariaceae). Journal of medicinal food, 13(5), 1147-1152.
• Alipieva, K., Korkina, L., Orhan, I. E., & Georgiev, M. I. (2014). Verbascoside—A review of its occurrence,(bio) synthesis and pharmacological significance. Biotechnology advances, 32(6), 1065-1076.
• Vertuani, S., Beghelli, E., Scalambra, E., Malisardi, G., Copetti, S., Toso, R. D., Baldisserotto, A., & Manfredini, S. (2011). Activity and stability studies of verbascoside, a novel antioxidant, in dermo-cosmetic and pharmaceutical topical formulations. Molecules, 16(8), 7068-7080. vyas
• Khullar, M., Sharma, A., Wani, A., Sharma, N., Sharma, N., Chandan, B., Kumar, A., & Ahmed, Z. (2019). Acteoside ameliorates inflammatory responses through NFkB pathway in alcohol induced hepatic damage. International immunopharmacology, 69, 109-117.
• Daneshforouz, A., Nazemi, S., Gholami, O., Kafami, M., & Amin, B. (2021). The cytotoxicity and apoptotic effects of verbascoside on breast cancer 4T1 cell line. BMC Pharmacology and Toxicology, 22(1), 72.
• Bilecenoğlu, D. K., & Yalçın, F. N. (2023). Lamium sp. In Medicinal Plants of Turkey (pp. 118-127). CRC Press.
• Yalçin, F. N., & Kaya, D. (2006). Ethnobotany, pharmacology and phytochemistry of the genus Lamium (Lamiaceae). Fabad Journal of Pharmaceutical Sciences, 31(1), 43.
• Ren, Y., He, J., Zhao, W., & Ma, Y. (2022). The anti-tumor efficacy of verbascoside on ovarian cancer via facilitating CCN1-AKT/NF-κB pathway-mediated M1 macrophage polarization. Frontiers in oncology, 12, 901922.
• Jia, W.-Q., Wang, Z.-T., Zou, M.-M., Lin, J.-H., Li, Y.-H., Zhang, L., & Xu, R.-X. (2018). Verbascoside inhibits glioblastoma cell proliferation, migration and invasion while promoting apoptosis through upregulation of protein tyrosine phosphatase SHP-1 and inhibition of STAT3 phosphorylation. Cellular Physiology and Biochemistry, 47(5), 1871-1882.
• Güner, A., Özhatay, N., Ekim, T., Başer, K. H. C., Hedge, I. C., & Hedge, I. C. (2000). Flora of Turkey and the East Aegean Islands: Volume 11, Supplement 2. Edinburgh University Press.
• Öztürk, M., Altay, V., & Keskin, M. (2023). Folkloric Knowledge of Endemic Plants: Their Traditional Uses as Spices, Food and Herbal Teas by the Local Communities in Turkiye. In Ethnic Knowledge and Perspectives of Medicinal Plants (pp. 137-152). Apple Academic Press.
• Bardakci, H., Cevik, D., Barak, T. H., Gozet, T., Kan, Y., & Kirmizibekmez, H. (2020). Secondary metabolites, phytochemical characterization and antioxidant activities of different extracts of Sideritis congesta PH Davis et Hub.-Mor. Biochemical Systematics and Ecology, 92, 104120.
• Öztürk Sarıkaya, S. B., & Zehiroğlu, C. (2025). Chemical Composition and Bioactivities of Sideritis libanotica Labill subsp. Libanotica: LC–HRMS Phytochemical Profiling, Mineral Content, Antioxidant, Antibacterial, and Neuroprotective–Antidiabetic Enzyme Inhibitory Potentials. Chemistry & Biodiversity, e01314.
• González-Burgos, E., Carretero, M., & Gómez-Serranillos, M. (2011). Sideritis spp.: Uses, chemical composition and pharmacological activities—A review. Journal of ethnopharmacology, 135(2), 209-225.
• Karamenderes, C., Konyalioglu, S., Khan, S., & Khan, I. A. (2007). Total phenolic contents, free radical scavenging activities and inhibitory effects on the activation of NF‐kappa B of eight Centaurea L. species. Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives, 21(5), 488-491.
• Sharonova, N., Nikitin, E., Terenzhev, D., Lyubina, A., Amerhanova, S., Bushmeleva, K., Rakhmaeva, A., Fitsev, I., & Sinyashin, K. (2021). Comparative assessment of the phytochemical composition and biological activity of extracts of flowering plants of Centaurea cyanus L., Centaurea jacea L. and Centaurea scabiosa L. Plants, 10(7), 1279.
• Milošević, T., Argyropoulou, C., Solujić, S., Murat-Spahić, D., & Skaltsa, H. (2010). Chemical composition and antimicrobial activity of essential oils from Centaurea pannonica and C. jacea. Natural product communications, 5(10), 1934578X1000501030.
• Uzun, A., Uzun, S. P., & Durmaz, A. (2019). Spatial analyses of Astragalus species distribution and richness in Kahramanmaraş (Turkey) by geographical information systems (GIS). Turkish Journal of Forest Science, 3(1), 37-59.
• Dai, Y., Wang, D., Zhao, M., Yan, L., Zhu, C., Li, P., Qin, X., Verpoorte, R., & Chen, S. (2020). Quality markers for Astragali radix and its products based on process analysis. Frontiers in pharmacology, 11, 554777.
• Liang, Y., Chen, B., Liang, D., Quan, X., Gu, R., Meng, Z., Gan, H., Wu, Z., Sun, Y., & Liu, S. (2023). Pharmacological effects of astragaloside IV: a review. Molecules, 28(16), 6118.
• Yang, Y., Hong, M., Lian, W.-W., & Chen, Z. (2022). Review of the pharmacological effects of astragaloside IV and its autophagic mechanism in association with inflammation. World journal of clinical cases, 10(28), 10004.
• Dinçman, G. E., Aytaç, Z., & Çalış, İ. (2024). Turkish Astragalus Species: Botanical Aspects, Secondary Metabolites, and Biotransformation. Planta medica.
• Sezik, E., Tabata, M., Yesilada, E., Honda, G., Goto, K., & Ikeshiro, Y. (1991). Traditional medicine in Turkey I. Folk medicine in northeast Anatolia. Journal of ethnopharmacology, 35(2), 191-196.
• Niemetz, R., & Gross, G. G. (2005). Enzymology of gallotannin and ellagitannin biosynthesis. Phytochemistry, 66(17), 2001-2011.
• Lee, H.-J., Seo, N.-J., Jeong, S.-J., Park, Y., Jung, D.-B., Koh, W., Lee, H.-J., Lee, E.-O., Ahn, K. S., & Ahn, K. S. (2011). Oral administration of penta-O-galloyl-β-D-glucose suppresses triple-negative breast cancer xenograft growth and metastasis in strong association with JAK1-STAT3 inhibition. Carcinogenesis, 32(6), 804-811.
• Başer, D. F., Akkol, E. K., Bozkurt, M., Süntar, İ., & Civelek, T. (2021). Hepatoprotective Effect of Pomegranate (Punica Granatum L.) in A Rabbit Model of Steatohepatitis. Kocatepe Veterinary Journal, 14(4), 507-519.
• Cai, D., Li, X., Chen, J., Jiang, X., Ma, X., Sun, J., Tian, L., Vidyarthi, S. K., Xu, J., & Pan, Z. (2022). A comprehensive review on innovative and advanced stabilization approaches of anthocyanin by modifying structure and controlling environmental factors. Food Chemistry, 366, 130611.
• Albrecht, M., Jiang, W., Kumi-Diaka, J., Lansky, E. P., Gommersall, L. M., Patel, A., Mansel, R. E., Neeman, I., Geldof, A. A., & Campbell, M. J. (2004). Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. Journal of medicinal food, 7(3), 274-283.
• Adhami, V. M., Khan, N., & Mukhtar, H. (2009). Cancer chemoprevention by pomegranate: laboratory and clinical evidence. Nutrition and cancer, 61(6), 811-815.
• Toi, M., Bando, H., Ramachandran, C., Melnick, S. J., Imai, A., Fife, R. S., Carr, R. E., Oikawa, T., & Lansky, E. P. (2003). Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo. Angiogenesis, 6(2), 121-128.
• Karin, M. (2009). NF-κB as a critical link between inflammation and cancer. Cold Spring Harbor perspectives in biology, 1(5), a000141.
• Scimeca, M., Urbano, N., Bonfiglio, R., Duggento, A., Toschi, N., Schillaci, O., & Bonanno, E. (2019). Novel insights into breast cancer progression and metastasis: A multidisciplinary opportunity to transition from biology to clinical oncology. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1872(1), 138-148.
• Carmeliet, P., & Jain, R. K. (2000). Angiogenesis in cancer and other diseases. Nature, 407(6801), 249-257.
• González, M. G., Janssen, A. P., IJzerman, A. P., Heitman, L. H., & van Westen, G. J. (2022). Oncological drug discovery: AI meets structure-based computational research. Drug discovery today, 27(6), 1661-1670.
• Bostancı, B., & Akalın, E. (2023). An overview of the therapeutic potentials and safety profiles of Berberis species in Türkiye. Turkish Journal of Biodiversity, 6(2), 159-166.
• Imanshahidi, M., & Hosseinzadeh, H. (2008). Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytotherapy research, 22(8), 999-1012.
• DeBlasi, J. M., & DeNicola, G. M. (2020). Dissecting the crosstalk between NRF2 signaling and metabolic processes in cancer. Cancers, 12(10), 3023.
• Salehi, B., Armstrong, L., Rescigno, A., Yeskaliyeva, B., Seitimova, G., Beyatli, A., Sharmeen, J., Mahomoodally, M. F., Sharopov, F., & Durazzo, A. (2019). Lamium plants—A comprehensive review on health benefits and biological activities. Molecules, 24(10), 1913.
• Polat, D. Ç., İlgün, S., Karatoprak, G. Ş., Akkol, E. K., & Capasso, R. (2022). Phytochemical profiles, antioxidant, cytotoxic, and anti-inflammatory activities of traditional medicinal plants: Centaurea pichleri subsp. pichleri, Conyza canadensis, and Jasminum fruticans. Molecules, 27(23), 8249.
• Raphael, B. J., Hruban, R. H., Aguirre, A. J., Moffitt, R. A., Yeh, J. J., Stewart, C., Robertson, A. G., Cherniack, A. D., Gupta, M., & Getz, G. (2017). Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer cell, 32(2), 185-203. e113.
• Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., & Saghafinia, S. (2018). Oncogenic signaling pathways in the cancer genome atlas. Cell, 173(2), 321-337. e310.
• Cox, A. D., & Der, C. J. (2025). “Undruggable KRAS”: druggable after all. Genes & development, 39(1-2), 132-162.
• Parikh, K., Banna, G., Liu, S. V., Friedlaender, A., Desai, A., Subbiah, V., & Addeo, A. (2022). Drugging KRAS: current perspectives and state-of-art review. Journal of hematology & oncology, 15(1), 152.
• Wade, M., Li, Y.-C., & Wahl, G. M. (2013). MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nature Reviews Cancer, 13(2), 83-96.
• O’Connor, M. J. (2015). Targeting the DNA damage response in cancer. Molecular cell, 60(4), 547-560.
• Lord, C. J., & Ashworth, A. (2017). PARP inhibitors: Synthetic lethality in the clinic. Science, 355(6330), 1152-1158.
• Kim, R. D., Sarker, D., Meyer, T., Yau, T., Macarulla, T., Park, J.-W., Choo, S. P., Hollebecque, A., Sung, M. W., & Lim, H.-Y. (2019). First-in-human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma. Cancer discovery, 9(12), 1696-1707.
• Österberg, F., Morris, G. M., Sanner, M. F., Olson, A. J., & Goodsell, D. S. (2002). Automated docking to multiple target structures: incorporation of protein mobility and structural water heterogeneity in AutoDock. Proteins: Structure, Function, and Bioinformatics, 46(1), 34-40.
• Rarey, M., Kramer, B., Lengauer, T., & Klebe, G. (1996). A fast flexible docking method using an incremental construction algorithm. Journal of molecular biology, 261(3), 470-489.
• Morris, G. M., Goodsell, D. S., Halliday, R. S., Huey, R., Hart, W. E., Belew, R. K., & Olson, A. J. (1998). Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of computational chemistry, 19(14), 1639-1662.
• Trott, O., & Olson, A. J. (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.
• Pettersen, E. F., Goddard, T. D., Huang, C. C., Meng, E. C., Couch, G. S., Croll, T. I., Morris, J. H., & Ferrin, T. E. (2021). UCSF ChimeraX: Structure visualization for researchers, educators, and developers. Protein Science, 30(1), 70-82.
• Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of computational chemistry, 30(16), 2785-2791.
• Hanwell, M. D., Curtis, D. E., Lonie, D. C., Vandermeersch, T., Zurek, E., & Hutchison, G. R. (2012). Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of cheminformatics, 4(1), 17.
• Kitchen, D. B., Decornez, H., Furr, J. R., & Bajorath, J. (2004). Docking and scoring in virtual screening for drug discovery: methods and applications. Nature reviews Drug discovery, 3(11), 935-949.
• Jones, G., Willett, P., Glen, R. C., Leach, A. R., & Taylor, R. (1997). Development and validation of a genetic algorithm for flexible docking. Journal of molecular biology, 267(3), 727-748.
• Warren, G. L., Andrews, C. W., Capelli, A.-M., Clarke, B., LaLonde, J., Lambert, M. H., Lindvall, M., Nevins, N., Semus, S. F., & Senger, S. (2006). A critical assessment of docking programs and scoring functions. Journal of medicinal chemistry, 49(20), 5912-5931.
• Jejurikar, B. L., & Rohane, S. H. (2021). Drug designing in discovery studio.
• Seeliger, D., & de Groot, B. L. (2010). Ligand docking and binding site analysis with PyMOL and Autodock/Vina. Journal of computer-aided molecular design, 24(5), 417-422.
• Burley, S. K., Berman, H. M., Christie, C., Duarte, J. M., Feng, Z., Westbrook, J., Young, J., & Zardecki, C. (2018). RCSB Protein Data Bank: Sustaining a living digital data resource that enables breakthroughs in scientific research and biomedical education. Protein Science, 27(1), 316-330.
• Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N., & Bourne, P. E. (2000). The protein data bank. Nucleic acids research, 28(1), 235-242.
• Hauschild, A.-C., Pastrello, C., Ekaputeri, G. K. A., Bethune-Waddell, D., Abovsky, M., Ahmed, Z., Kotlyar, M., Lu, R., & Jurisica, I. (2023). MirDIP 5.2: tissue context annotation and novel microRNA curation. Nucleic acids research, 51(D1), D217-D225.
• Anderson, A. C. (2003). The process of structure-based drug design. Chemistry & biology, 10(9), 787-797.
• Mishima, K., Kaneko, H., & Funatsu, K. (2014). Development of a new de novo design algorithm for exploring chemical space. Molecular Informatics, 33(11‐12), 779-789.
• Lionta, E., Spyrou, G., K Vassilatis, D., & Cournia, Z. (2014). Structure-based virtual screening for drug discovery: principles, applications and recent advances. Current topics in medicinal chemistry, 14(16), 1923-1938.
• Patricelli, M. P., Janes, M. R., Li, L.-S., Hansen, R., Peters, U., Kessler, L. V., Chen, Y., Kucharski, J. M., Feng, J., & Ely, T. (2016). Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer discovery, 6(3), 316-329.
• Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., & Klein, C. (2004). In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science, 303(5659), 844-848.
• Holzer, P., Masuya, K., Furet, P., Kallen, J., Valat-Stachyra, T., Ferretti, S., Berghausen, J., Bouisset-Leonard, M., Buschmann, N., & Pissot-Soldermann, C. (2015). Discovery of a dihydroisoquinolinone derivative (NVP-CGM097): a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors. In: ACS Publications.
• Kettner, N. M., Voicu, H., Finegold, M. J., Coarfa, C., Sreekumar, A., Putluri, N., Katchy, C. A., Lee, C., Moore, D. D., & Fu, L. (2016). Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer cell, 30(6), 909-924.
• Zhu, J.-Y., Cuellar, R. A., Berndt, N., Lee, H. E., Olesen, S. H., Martin, M. P., Jensen, J. T., Georg, G. I., & Schönbrunn, E. (2017). Structural basis of wee kinases functionality and inactivation by diverse small molecule inhibitors. Journal of medicinal chemistry, 60(18), 7863-7875.
• Joshi, J. J., Coffey, H., Corcoran, E., Tsai, J., Huang, C.-L., Ichikawa, K., Prajapati, S., Hao, M.-H., Bailey, S., & Wu, J. (2017). H3B-6527 is a potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma. Cancer research, 77(24), 6999-7013.
• Hagel, M., Miduturu, C., Sheets, M., Rubin, N., Weng, W., Stransky, N., Bifulco, N., Kim, J. L., Hodous, B., & Brooijmans, N. (2015). First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer discovery, 5(4), 424-437.
• Lin, X., Yosaatmadja, Y., Kalyukina, M., Middleditch, M. J., Zhang, Z., Lu, X., Ding, K., Patterson, A. V., Smaill, J. B., & Squire, C. J. (2019). Rotational freedom, steric hindrance, and protein dynamics explain BLU554 selectivity for the hinge cysteine of FGFR4. ACS medicinal chemistry letters, 10(8), 1180-1186.
• Ryan, K., Bolaňos, B., Smith, M., Palde, P. B., Cuenca, P. D., VanArsdale, T. L., Niessen, S., Zhang, L., Behenna, D., & Ornelas, M. A. (2021). Dissecting the molecular determinants of clinical PARP1 inhibitor selectivity for tankyrase1. Journal of biological chemistry, 296.
• Skoulidis, F., Li, B. T., Dy, G. K., Price, T. J., Falchook, G. S., Wolf, J., Italiano, A., Schuler, M., Borghaei, H., & Barlesi, F. (2021). Sotorasib for lung cancers with KRAS p. G12C mutation. New England Journal of Medicine, 384(25), 2371-2381.
• Adhikary, T., & Basak, P. (2024). In-silico approach to investigate the phytochemicals of terminalia arjuna as multitarget inhibitors of proteins involved with lung cancer. Letters in Drug Design & Discovery, 21(2), 329-338.
• Mahmoud, A., Elkhalifa, D., Alali, F., Al Moustafa, A.-E., & Khalil, A. (2020). Novel polymethoxylated chalcones as potential compounds against KRAS-mutant colorectal cancers. Current pharmaceutical design, 26(14), 1622-1633.
• Lei, H., Guo, M., Li, X., Jia, F., Li, C., Yang, Y., Cao, M., Jiang, N., Ma, E., & Zhai, X. (2020). Discovery of novel indole-based allosteric highly potent ATX inhibitors with great in vivo efficacy in a mouse lung fibrosis model. Journal of medicinal chemistry, 63(13), 7326-7346.
• Prinsa, Saha, S., Bulbul, M. Z. H., Ozeki, Y., Alamri, M. A., & Kawsar, S. M. (2024). Flavonoids as potential KRAS inhibitors: DFT, molecular docking, molecular dynamics simulation and ADMET analyses. Journal of asian natural Products research, 26(8), 955-992.
• Rajasegaran, T., How, C. W., Saud, A., Ali, A., & Lim, J. C. W. (2023). Targeting inflammation in non-small cell lung cancer through drug repurposing. Pharmaceuticals, 16(3), 451.
• Siddique, H. R., Liao, D. J., Mishra, S. K., Schuster, T., Wang, L., Matter, B., Campbell, P. M., Villalta, P., Nanda, S., & Deng, Y. (2012). Epicatechin‐rich cocoa polyphenol inhibits Kras‐activated pancreatic ductal carcinoma cell growth in vitro and in a mouse model. International Journal of Cancer, 131(7), 1720-1731.
• Wang, Y., Liu, Y., Du, X., Ma, H., & Yao, J. (2020). The anti-cancer mechanisms of berberine: A review. Cancer management and research, 695-702.
• Wang, K.-B., Liu, Y., Li, J., Xiao, C., Wang, Y., Gu, W., Li, Y., Xia, Y.-Z., Yan, T., & Yang, M.-H. (2022). Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine. Nature Communications, 13(1), 6016.
• Lohberger, B., Glänzer, D., Kaltenegger, H., Eck, N., Leithner, A., Bauer, R., Kretschmer, N., & Steinecker-Frohnwieser, B. (2022). Shikonin derivatives cause apoptosis and cell cycle arrest in human chondrosarcoma cells via death receptors and MAPK regulation. BMC cancer, 22(1), 758.
• Hao, G., Zhai, J., Jiang, H., Zhang, Y., Wu, M., Qiu, Y., Fan, C., Yu, L., Bai, S., & Sun, L. (2020). Acetylshikonin induces apoptosis of human leukemia cell line K562 by inducing S phase cell cycle arrest, modulating ROS accumulation, depleting Bcr-Abl and blocking NF-κB signaling. Biomedicine & Pharmacotherapy, 122, 109677.
• Han, R., Yang, H., Ling, C., & Lu, L. (2022). Tiliroside suppresses triple-negative breast cancer as a multifunctional CAXII inhibitor. Cancer Cell International, 22(1), 368.
• Azme, E., Hasan, M. M., Ali, M. L., Alam, R., Hoque, N., Noushin, F., Kabir, M. F., Islam, A., Nipun, T. S., & Hossen, S. M. (2025). Computational identification of potential natural terpenoid inhibitors of MDM2 for breast cancer therapy: molecular docking, molecular dynamics simulation, and ADMET analysis. Frontiers in Chemistry, 13, 1527008.
• Basha, N. J., Akshay, K., Mohan, R., Javeed, M., & Sharma, O. M. (2025). Synthesis, molecular docking, drug likeness, in silico toxicity and DFT studies of small molecules as p53-MDM2 interaction and COX-2 dual inhibitors. Journal of Molecular Structure, 1322, 140393.
• Oraibi, A. I., Dawood, A. H., Debbabi, N., Almukram, A. M. A., Almaary, K. S., Dabiellil, F., Chekir-Ghedira, L., & Kilani-Jaziri, S. (2025). Resveratrol-derived MDM2 inhibitors: Synthesis, characterization, and biological evaluation against MDM2 and HCT-116 cells. Open Chemistry, 23(1), 20250142.
• Shoaib, T. H., Abdelmoniem, N., Mukhtar, R. M., Alqhtani, A. T., Alalawi, A. L., Alawaji, R., Althubyani, M. S., Mohamed, S. G., Mohamed, G. A., & Ibrahim, S. R. (2023). Molecular docking and molecular dynamics studies reveal the anticancer potential of medicinal-plant-derived lignans as MDM2-P53 interaction inhibitors. Molecules, 28(18), 6665.
• da Mota, V. H. S., de Melo, F. F., de Brito, B. B., da Silva, F. A. F., & Teixeira, K. N. (2022). Molecular docking of DS-3032B, a mouse double minute 2 enzyme antagonist with potential for oncology treatment development. World Journal of Clinical Oncology, 13(6), 496.
• Gounder, M. M., Bauer, T. M., Schwartz, G. K., Weise, A. M., LoRusso, P., Kumar, P., Tao, B., Hong, Y., Patel, P., & Lu, Y. (2023). A first-in-human phase I study of milademetan, an MDM2 inhibitor, in patients with advanced liposarcoma, solid tumors, or lymphomas. Journal of clinical oncology, 41(9), 1714-1724.
• Shiferaw, D. G., & Kalluraya, B. (2024). Synthesis, characterization, biological evaluation, and molecular docking studies of new 1, 3, 4-oxadiazole-thioether derivative as antioxidants and cytotoxic agents. Heliyon, 10(7).
• Takebe, N., Naqash, A. R., O'Sullivan Coyne, G., Kummar, S., Do, K., Bruns, A., Juwara, L., Zlott, J., Rubinstein, L., & Piekarz, R. (2021). Safety, antitumor activity, and biomarker analysis in a phase I trial of the once-daily Wee1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors. Clinical Cancer Research, 27(14), 3834-3844.
• Lheureux, S., Cristea, M. C., Bruce, J. P., Garg, S., Cabanero, M., Mantia-Smaldone, G., Olawaiye, A. B., Ellard, S. L., Weberpals, J. I., & Hendrickson, A. E. W. (2021). Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial. The Lancet, 397(10271), 281-292.
• Leijen, S., van Geel, R. M., Sonke, G. S., de Jong, D., Rosenberg, E. H., Marchetti, S., Pluim, D., van Werkhoven, E., Rose, S., & Lee, M. A. (2016). Phase II study of WEE1 inhibitor AZD1775 plus carboplatin in patients with TP53-mutated ovarian cancer refractory or resistant to first-line therapy within 3 months. Journal of clinical oncology, 34(36), 4354-4361.
• Pandey, P., Lakhanpal, S., Mahmood, D., Kang, H. N., Kim, B., Kang, S., Choi, J., Moon, S., Pandey, S., & Ballal, S. (2025). Bergenin, a bioactive flavonoid: advancements in the prospects of anticancer mechanism, pharmacokinetics and nanoformulations. Frontiers in pharmacology, 15, 1481587.
• Yamamoto, G., Tanaka, K., Kamata, R., Saito, H., Yamamori-Morita, T., Nakao, T., Liu, J., Mori, S., Yagishita, S., & Hamada, A. (2025). WEE1 confers resistance to KRASG12C inhibitors in non-small cell lung cancer. Cancer letters, 611, 217414.
• Yildirim, M., Cimentepe, M., Dogan, K., Necip, A., & Amangeldinova, M. (2025). Next-generation antibacterial cryogels: Berberine-infused smart membranes with molecular docking-guided targeting of MRSA and MDR E. coli. Biophysical Chemistry, 107481.
• Wang, Y., Liu, Q., Liu, Z., Li, B., Sun, Z., Zhou, H., Zhang, X., Gong, Y., & Shao, C. (2012). Berberine, a genotoxic alkaloid, induces ATM-Chk1 mediated G2 arrest in prostate cancer cells. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 734(1-2), 20-29.
• Lin, C.-C., Lin, S.-Y., Chung, J.-G., Lin, J.-P., Chen, G.-W., & Kao, S.-T. (2006). Down-regulation of cyclin B1 and up-regulation of Wee1 by berberine promotes entry of leukemia cells into the G2/M-phase of the cell cycle. Anticancer Research, 26(2A), 1097-1104.
• Hu, X., Wu, X., Huang, Y., Tong, Q., Takeda, S., & Qing, Y. (2014). Berberine induces double-strand DNA breaks in Rev3 deficient cells. Molecular medicine reports, 9(5), 1883-1888.
• Xu, J., Cui, J., Jiang, H., Zeng, Y., & Cong, X. (2023). Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients. Cancer Medicine, 12(7), 7762-7771.
• Fan, L., Xie, H., Wang, W., Peng, G., Fu, Z., & Ye, Q. (2025). Structure-based identification of potent fibroblast growth factor receptor 4 (FGFR4) inhibitors as potential therapeutics for hepatocellular carcinoma. PeerJ, 13, e19183.
• Schwarz, M., Kurkunov, M., Wittlinger, F., Rudalska, R., Wang, G., Schwalm, M. P., Rasch, A., Wagner, B., Laufer, S. A., & Knapp, S. (2024). Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles. Journal of medicinal chemistry, 67(8), 6549-6569.
• Zandarashvili, L., Langelier, M.-F., Velagapudi, U. K., Hancock, M. A., Steffen, J. D., Billur, R., Hannan, Z. M., Wicks, A. J., Krastev, D. B., & Pettitt, S. J. (2020). Structural basis for allosteric PARP-1 retention on DNA breaks. Science, 368(6486), eaax6367.