Discovery of Naturally Occurring Flavonoids as Human Cytochrome P450 (CYP3A4) Inhibitors with the Aid of Computational Chemistry

Abstract

Purpose: The human cytochrome P450 3A4 (CYP3A4) is the biggest individual from the CYP3A subfamily and records for 30–60% of the total for CYP450 adult liver. Hereditary varieties in CYP3A4 are a noteworthy hotspot for inter-patient changeability in plasma concentration, adverse effects and pharmacological response to medications. This research was done to discover naturally occurring novel CYP3A4 inhibitors from flavonoids. Methods: The molecular docking method was used to optimize the inhibiting activity of flavonoids against CYP3A4. PyRx Virtual Screening Tool 0.8 and BIOVIA Discovery Studio 2019 was used for simulation. Results: Flavonoids like Pongamoside A, Pongamoside B, and Pongamoside D have more binding affinity (kcal/mol) i.e. -11.6, -10.9, -10.8 respectively than Doxorubicin which have -10.7 against CYP3A4. Although, Daidzein, Genistein, and Luteolin form more hydrogen bonds than doxorubicin. Conclusion: The rational synthesis of natural analogues in reference to synthetic drugs, could generate drugs with improved therapeutic effect for chemoprevention. CYP3A4 plays a major role in the metabolism of various drugs; by the help of flavonoids, we can control the selective drug metabolism by inhibiting CYP3A4. Despite this, these molecules are not marketed for cancer treatment because of high polarity. If we could overcome this problem, these molecules can acts as effective anticancer agents in the future. Still, if we want to use these compounds clinically, there is a need to generate more scientific evidence and quality data by using in vivo and in vitro models. © 2020 iGlobal Research and Publishing Foundation. All rights reserved. Cite this article as: Khan, S.L.; Sonwane, G.M.; Siddiqui, F.A.; Jain, S.P.; Kale, M.A.; Borkar, V.S. Discovery of naturally occurring flavonoids as human cytochrome P450 (CYP3A4) inhibitors with the aid of computational chemistry. Indo Global J. Pharm. Sci., 2020; 10(4): 58-69. DOI: http://doi.org/10.35652/IGJPS.2020.10409 . Indo Global Journal of Pharmaceutical Sciences, 2020; 10(4): 58-69 59 inflammatory, antiallergic, modulators of enzymatic activities and anti-cancer activity [3]. Apigenin, luteolin, quercetin and kaempferol, the hydroxylated flavonoids are the main constituents of various dietary products and beverages and have been the focus of extensive research over the last years. Apigenin exerts anticancer effects through the modulation of various pathways namely, apoptosis, Reactive oxygen species (ROS) and DNA damage and repair[4]. Malignant growth is one of the terrible illnesses caused by unusual cell growth and can attack different tissues. They shape a subset of neoplasms. It speaks of the greatest social insurance issues for humankind and requests a proactive system for cure [5]. It is accounted for the rate of malignancy that has been expanding in developing nations and has turned into the fourth driving reason for death around the world. Chemoprevention by phytoconstituents has advanced as a powerful procedure to control the prevalence of malignant growth. The journey of anticancer agents from plant sources began in the 1950s with the discovery of the vinca alkaloids, vincristine, vinblastine, combretastatin, and colchicine. These Phytochemicals act explicitly on tumor cells without influencing non-cancerous cells. Carcinogenesis is a mindboggling marvel that includes many signaling cascades. Phytochemicals are viewed as reasonable candidates for anticancer medication advancement due to their pleiotropic activities on target. The examination is in advancement for creating potential competitors (those can square or back off the development of disease cells without any side effects) from these phytochemicals. Numerous phytochemicals and their determined analogs have been distinguished as potential candidates for anticancer treatment. Plants serve as a source of novel compound elements and give a promising line to investigate on malignant growth. The plant and plant metabolites are the reforming sources as these are simple, more secure, easy, quick, and less dangerous as contrasted to traditional treatment methods. There is a positive relationship set up by the epidemiological examinations between expanded utilization of common items with diminished danger of disease. The mechanism responsible for chemoprevention remains essentially unidentified, however, it is likely identified with the closeness of phytochemicals related to plants. Consequently, the search for powerful and more secure natural anticancer agents have attracted the researchers throughout the world. [6,7]. The human cytochrome P450 3A4 (CYP3A4) is the biggest individual from the CYP3A subfamily and records for 30– 60% of the total for CYP450 adult liver. The CYP3A4 gene is limited on chromosome 7q21 and up to now, 41 CYP3A4 alleles have been recognized. The human CYP3A locus contains the three CYP3A gene (CYP3A4, CYP3A5, and CYP3A7), three pseudogenes, and a novel CYP3A gene named CYP3A43. Hereditary varieties in CYP3A4 are a noteworthy hotspot for inter-patient changeability in plasma concentration, adverse effects and pharmacological response to medications, for example, paclitaxel, fentanyl, tamoxifen, tacrolimus, and statins. Moreover, existing investigations have announced the role of CYP3A4 inadequate alleles in the disease susceptibility to prostate malignant growth, estrogen receptor-negative breast cancer, and type-2 diabetes [8,9]. Protein-ligand docking is a fundamental part of computeraided drug design, and it distinguishes the coupling pattern of proteins and ligands by computer simulation. Molecular docking results decide a general binding mode of a ligand. Varieties of compounds from plant sources have been accounted to have significant anticancer properties; in any case, their modes of activity have not been characterized. Molecular docking studies were performed on some flavonoids by using Autodock vina 1.1.2 in PyRx 0.8. [10]. The docking was performed utilizing receptor proteins required with cell cycle, cell development, and DNA replication, i.e., cyclin-subordinate protein kinase 2 (CDK-2), CDK-6, DNA topoisomerases I and II, B-cell lymphoma 2 (Bcl-2), vascular endothelial development factor receptor 2 (VEGFR-2), and the telomere: G-quadruplexes. By molecular docking, the bound confirmations and the coupling attachment among flavonoid and CYP3A4 as the target could be anticipated [11]. Doxorubicin, sold under the brand names adriamycin, used to treat breast malignant growth, bladder cancer, lymphoma, and intense lymphocytic leukemia was utilized for docking studies whose binding interactions were compared with the flavonoids [12]. Docking of the small molecule into the binding site of a receptor and guessing the binding interaction of the complex is a noteworthy part of the structure-based drug design process. By molecular docking, the bound conformations and the binding affinity between Flavonoids and human cytochrome P450 3A4 as the target could be predicted [13]. Table 1 represents the names and structures of doxorubicin and the flavonoids used for molecular docking. The structures of all the compounds were generated by using ChemDraw Ultra 8.0 with the help of IUPAC name took from the official website of U.S. National Library of Medicine PubChem (https://pubchem.ncbi.nlm.nih.gov/). Indo Global Journal of Pharmaceutical Sciences, 2020; 10(4): 58-69 60 Table 1. Name and Structures of compounds used for molecular docking Doxorubicin Pongamoside A Pongamoside B