Abstract
A tyrosine kinase receptor known as epidermal growth factor receptor (EGFR) is one of the main tumour markers in many cancer types and also plays a crucial role in cell proliferation, differentiation, angiogenesis, and apoptosis, which is a result of the auto-phosphorylations (kinase activity enhancement) that trigger signals involved in different cellular processes. Due to the discovery that non-small cell lung cancer (NSCLC) is a cause of this kinase activity enhancement, so far, several inhibitors have been tested against EGFR, but the side effects of these inhibitors necessitate an urgent measure to come up with an inhibitor that will be more specific to the cancer cells and not affect self-cells. This study was conducted to evaluate the efficacy of 37 compounds derived from Piper nigrum against EGFR using computer-aided drug design. Based on molecular docking, induced-fit docking, calculation of free binding energy, pharmacokinetics, QSAR prediction, and MD simulation. We propose five (5) lead compounds (clarkinol A, isodihydrofutoquinol B, Burchellin, kadsurin B, and lancifolin C) as a novel inhibitor, with clarkinol A demonstrating the highest binding affinity (−7.304 kcal/mol) with EGFR when compared with the standard drug (erlotinib). They also showed significant moderation for parameters investigated for a good pharmacokinetic profile, with a reliable R2 coefficient value predicted using QSAR models. The MD simulation of clarkinol A was found to be stable within the EGFR binding pocket throughout the 75 ns simulation run time. The findings showed that clarkinol A derived from Piper nigrum is worth further investigation and consideration as a possible EGFR inhibitor for the treatment of lung cancer.
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References
Acharya SG, Momin AH, Gajjar AV (2012) Review of piperine as a bio-enhancer. Amer J PharmTech Res 2:32–44
Ahmad N, Fazal H, Abbasi B, Farooq S, Ali M, Khan M (2012a) Biological role of Piper nigrum L. (Black pepper): a review. Asian Pac J Trop Biomed 2(3):S1945
Ahmad N, Fazal H, Abbasi BH, Farooq S, Ali M et al (2012) Biological role of Piper nigrum L. (Black pepper): A review. Asian Pacific Journal of Tropical Biomedicine: S1945-S1953
Beniston M (2011) ‘Alps’, Encyclopedia of Earth Sciences Series, Part 3, 35–38, doi: https://doi.org/10.1007/978-90-481-2642-2_16
Carcereny E, Morán T, Capdevila L, Cros S, Vilà L et al (2015) The epidermal growth factor receptor (EGRF) in lung cancer. Trans Respir Med 3(1):1. https://doi.org/10.1186/s40247-015-0013-z
Schrödinger Release 2018–2: Maestro, Schrödinger, LLC, New York, NY, 2018.
Cruz CS, Tanoue LT, Matthay RA (2011) Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 32(4):605–644. https://doi.org/10.1016/j.ccm.2011.09.001
Daina A, Michielin O, Zoete V et al (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7(1):42717
de Oliveira MT, Katekawa E (2017) On the virtues of automated QSAR—the new kid on the block. Future Med Chem. https://doi.org/10.4155/FMC-2017-0170
Dixon SL, Duan J, Smith E, Von Bargen CD, Sherman W, Repasky MP (2016) AutoQSAR: an automated machine learning tool for best-practice QSAR modeling. Future Med Chem 8:1825–1839
Genheden S, Ryde U (2015) The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov 10:449–461
Hadni H, Elhallaoui M (2020) 3D-QSAR, docking and ADMET properties of aurone analogues as antimalarial agents. Heliyon 6(4):e03580
Haq IU, Imran M, Nadeem M, Tufail T, Gondal TA, Mubarak MS (2021) Piperine: A review of its biological effects. Phytother Res 35(2):680–700
Inamura K, Ninomiya H, Ishikawa Y, Matsubara O (2010) Is the epidermal growth factor receptor status in lung cancers reflected in clinicopathologic features? Arch Pathol Lab Med 134:66–72
Iwaloye O, Elekofehinti OO, Oluwarotimi EA, Babatomiwa K, Momoh I (2020) Insilico molecular studies of natural compounds as possible anti-Alzheimer’s agents: ligand-based design. Netw Model Anal Health Inform Bioinform 9:54
Johnson JJ, Nihal M, Siddiqui IA, Scarlett CO, Bailey HH et al (2011) Enhancing the bioavailability of resveratrol by combining it with piperine. Mol Nutr Food Res 55:1169–1176
Maione P, Sacco PC, Sgambato A, Casaluce F, Rossi A, Gridelli C (2015) Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application. Ther Adv Med Oncol 7(5):263–273
Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC (2012) Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 13(5):528–538. https://doi.org/10.1016/S1470-2045(12)70087-6
Nandi S, Bagchi MC (2010) 3D-QSAR and molecular docking studies of 4-anilinoquinazoline derivatives: A rational approach to anticancer drug design. Mol Diversity 14:27–38
Nandi S, Bagchi MC (2011) In silico design of potent EGFR kinase inhibitors by structure-based screening of combinatorial libraries. Mol Simul 37:196–209
Nandi S, Bagchi MC (2016) EGFr, FGFr and PDGFr: emerging targets for anticancer drug design. J Cancer Res 5:99–108
Nandi S, Dey R, Samadder A, Saxena AK (2022a) Natural sourced inhibitors of EGFR, PDGFR, FGFR and VEGFR-mediated signaling pathways as potential anticancer agents. Curr Med Chem 29(2):212–234
Nandi S, Dey R, Dey S, Samadder A, Saxena AK (2022b) Naturally sourced CDK inhibitors and current trends in structure-based synthetic anticancer drug design by crystallography. Anticancer Agents Med Chem 22(3):485–498
Paarakh PM, Sreeram DC (2015) In vitro cytotoxic and in silico activity of piperine isolated from Piper nigrum fruits Linn. In Silico Pharmacology 3(1):9. https://doi.org/10.1186/s40203-015-0013-2
Parganiha R, Verma S, Chandrakar S, Pal S, Sawarkar HA, Kashyap P (2011) In vitro anti- asthmatic activity of fruit extract of Piper nigrum (Piperaceae). Int J Herbs Pharmacol Res 1:15–18
Sastry M, Lowrie JF, Dixon SL, Sherman W (2010) Large-scale systematic analysis of 2D fingerprint methods and parameters to improve virtual screening enrichments. J Chem Inf Model 50:771–784
Schrank Z, Chhabra G, Lin L, Iderzorig T, Osude C, Khan N, Kuckovic A, Singh S, Miller RJ, Puri N (2018) Current molecular-targeted therapies in NSCLC and their mechanism of resistance. Cancers 10(7):224
Schrödinger Release 201 8–4: LigPrep (2018) Schrödinger. LLC, New York, NY. 2018
Schrödinger Release 2020–2: Induced Fit Docking protocol; Glide, Schrödinger, LLC, New York, NY (2016) Prime, Schrödinger, LLC, New York, NY, 2020
Schrödinger Release 2020–2: Prime, Schrödinger. New York, NY: LLC, 2020.
Sitki-Copur M (2019) State of cancer research around the globe. Oncol J 33(5):181–185
Schrödinger Suite (2012) Protein Preparation Wizard; Epik version 2.3, Schrödinger, LLC, New York, NY, 2012; Impact version 5.8, Schrödinger, LLC, New York, NY, 2012; Prime version 3.1, Schrödinger, LLC, New York, NY, 2012.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249
Vijayakumar S, Manogar P, Prabhu S, Singh RAS (2018) Novel ligand-based docking; molecular dynamic simulations; and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer’s disease. J Pharm Anal 8:413–420
Yun CH, Boggon TJ, Li Y, Woo S, Greulich H, Meyerson M, Eck MJ (2007) Structures of lung cancer-derived Egfr mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11:217
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O.O.E, I.F.R and H.O.P wrote the main manuscript, F.O.A, F.A.T, I.F.R and A.E.A worked on software and data analysis. M.O.A and O.F.K reviewed and edited the manuscript. O.O.E and O.I. designed the work
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Elekofehinti, O.O., Adetoyi, I.R., Popoola, H.O. et al. Discovery of potential epidermal growth factor receptor inhibitors from black pepper for the treatment of lung cancer: an in-silico approach. In Silico Pharmacol. 12, 28 (2024). https://doi.org/10.1007/s40203-024-00197-1
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DOI: https://doi.org/10.1007/s40203-024-00197-1