Xavier University of Louisiana XULA Digital Commons Faculty and Staff Publications 4-24-2019 Coumarins and P450s, Studies Reported to-Date Maryam Foroozesh Xavier University of Louisiana, [email protected] Jayalakshmi Sridhar Xavier University of Louisiana, [email protected] Navneet Goyal Xavier University of Louisiana, [email protected] Jiawang Liu University of Tennessee Health Science Center, [email protected] Follow this and additional works at: https://digitalcommons.xula.edu/fac_pub Part of the Medicinal-Pharmaceutical Chemistry Commons Recommended Citation Foroozesh, Maryam; Sridhar, Jayalakshmi; Goyal, Navneet; and Liu, Jiawang, "Coumarins and P450s, Studies Reported to-Date" (2019). Faculty and Staff Publications. 42. https://digitalcommons.xula.edu/fac_pub/42 This Article is brought to you for free and open access by XULA Digital Commons. It has been accepted for inclusion in Faculty and Staff Publications by an authorized administrator of XULA Digital Commons. For more information, please contact [email protected]. molecules Review Coumarins and P450s, Studies Reported to-Date Maryam Foroozesh 1,*, Jayalakshmi Sridhar 1, Navneet Goyal 1 and Jiawang Liu 2 1 Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125, USA; [email protected] (J.S.); [email protected] (N.G.) 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Ave., Memphis, TN 38163, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-504-520-5078; Fax: +1-504-520-7942 Academic Editor: Salvatore Genovese Received: 9 April 2019; Accepted: 22 April 2019; Published: 24 April 2019 Abstract: Cytochrome P450 enzymes (CYPs) are important phase I enzymes involved in the metabolism of endogenous and xenobiotic compounds mainly through mono-oxygenation reactions into more polar and easier to excrete species. In addition to their role in detoxification, they play important roles in the biosynthesis of endogenous compounds and the bioactivation of xenobiotics. Coumarins, phytochemicals abundant in food and commonly used in fragrances and cosmetics, have been shown to interact with P450 enzymes as substrates and/or inhibitors. In this review, these interactions and their significance in pharmacology and toxicology are discussed in detail. Keywords: cytochrome P450; coumarins; docking; quantitative structure-activity relationship (QSAR); hologram quantitative structure-activity relationship (HQSAR); comparative molecular field analysis (CoMFA); comparative molecular similarity index analysis (CoMSIA); molecular modeling; active site; competitive inhibition; time-dependent inhibition 1. Introduction 1.1. Cytochrome P450s Enzymes Cytochrome P450 enzymes (CYPs), an important superfamily of Phase I enzymes, are involved in the metabolism of endogenous and exogenous (xenobiotic) compounds [1–4]. These versatile enzymes are found in all living organisms and catalyze the mono-oxygenation of a wide variety of substrates [1]. The primary purpose of P450s is detoxification by oxidizing non-polar molecules into more polar and excretable ones [5]. Mammalian P450s play important roles in cholesterol and hormone synthesis, metabolism of endogenous compounds such as vitamin D and bile acids, drug activation and deactivation, and xenobiotic detoxification [1–4]. About 75% of known enzymatic reactions on drugs are catalyzed by P450 enzymes [6]. In addition, these enzymes play an important role in carcinogenesis, as certain pro-carcinogenic compounds are metabolized by P450 enzymes into their ultimate carcinogenic forms, which are capable of binding DNA and initiating cancer [1,7,8]. P450s are estimated to catalyze about 66% of bioactivation reactions, many of which lead to cancer formation [9–11]. The Human Genome Project has shown that there are 57 human P450 genes and 58 pseudogenes [1,12]. As more substrates including environmental chemicals and drugs have been discovered for the various P450 enzymes, their versatility and importance have become more apparent, warranting additional studies on their mechanisms of action and roles in different diseases including cancer. The development of selective inhibitors for P450 enzymes involved in carcinogenesis has been the focus of many research groups, including ours and our collaborators [13–23]. Molecules 2019, 24, 1620; doi:10.3390/molecules24081620 www.mdpi.com/journal/molecules Molecules 2019, 24, 1620 2 of 17 Molecules 2019, 24, x FOR PEER REVIEW 2 of 17 1.1.1. Basic Enzyme Structure 1.1.1.P450 Basic Enzymes Enzyme are Structure a superfamily of hemoproteins [1]. Even though the amino acid sequence identityP450 across Enzymes the entire are P450a superfamily superfamily of hemoproteins is less than 20%, [1]. Even the enzymes though the have amino identical acid overallsequence fold structures.identity across The three-dimensional the entire P450 superfamily structure is of le P450sss than consists 20%, the of enzymes 12 α-helices have (A-L), identical forming overall the fold bulk ofstructures. the protein, The in three-dimensional addition to four βstructure-sheets. of The P450s heme consists is located of 12 α within-helices the (A-L), L-helix forming and the bulk highly conservedof the protein, I-helix in that addition is perpendicular to four β-sheets. to the The F/G heme segment is located made within from the the F-helix, L-helix Fand/G-loop the highly and the G-helixconserved [23]. I-helix The heme-Fe that is perpendicular atom is bound to to the the F/ sulfurG segment atom made of the from cysteine the F-helix, amino acidF/G-loop in the and adjacent the loop,G-helix which [23]. contains The heme-Fe the highly atom conserved is bound sequenceto the sulfur FxxGx(HRK)xCxG atom of the cysteine [23]. Substrateamino acid access in the and specificityadjacent forloop, the which various contains P450 active the highly sites arecons determinederved sequence by the FxxGx(HR B-C andK)xCxG F-G helices [23]. [ 23Substrate]. Crystal structuresaccess and of manyspecificity P450 for enzymes the various have P450 already active been sites published are determined [24–31]. by the B-C and F-G helices [23]. Crystal structures of many P450 enzymes have already been published [24–31]. 1.1.2. Catalytic Activity Cycle 1.1.2. Catalytic Activity Cycle The catalytic activity starts once a substrate is bound to the enzyme, and the low-spin ferric heme-ironThe (coordinatedcatalytic activity to a waterstarts moleculeonce a substrate as its sixth is bound ligand to in the its restingenzyme, state) and changes the low-spin to a high-spin ferric ferricheme-iron state in (coordinated the enzyme-substrate to a water complex.molecule Theas its heme-iron sixth ligand then in its binds resting an oxygenstate) changes molecule to a to high- form a spin ferric state in the enzyme-substrate complex. The heme-iron then binds an oxygen molecule to stable oxy-iron-enzyme complex. This oxy-iron-enzyme complex is then reduced to form an unstable form a stable oxy-iron-enzyme complex. This oxy-iron-enzyme complex is then reduced to form an peroxo-ferric-enzyme complex, followed by the protonation of the distal oxygen to form an unstable unstable peroxo-ferric-enzyme complex, followed by the protonation of the distal oxygen to form hydroperoxo-iron-enzyme complex. A second protonation of the same oxygen is then followed by an unstable hydroperoxo-iron-enzyme complex. A second protonation of the same oxygen is then heterolytic cleavage of the bond between the two oxygen atoms leading to the formation of a reactive followed by heterolytic cleavage of the bond between the two oxygen atoms leading to the high-valentformation iron-oxo-enzymeof a reactive high-valent complex iron-oxo-e and water.nzyme This complex complex and then water. abstracts This a complex hydrogen then atom fromabstracts the substrate a hydrogen with atom subsequent from the radical substrate recombination with subsequent to form radical the product recombination (oxidized to formform ofthe the substrate).product (oxidized After the releaseform of ofthe the substrate). product, After water the binds release to the of heme-iron,the product, regenerating water binds the to the resting heme- P450 enzymeiron, regenerating (Figure1)[1 ,the23]. resting P450 enzyme (Figure 1) [1,23]. FigureFigure 1. The1. The catalytic catalytic oxidation oxidation cycle cycle of cytochrome of cytoch P450rome enzymes—TheP450 enzymes—The heme-Fe heme-Fe atom is covalentlyatom is boundcovalently to the bound sulfur to atom the ofsulfur a cysteine atom of amino a cysteine acid amino residue acid in theresidue enzyme in the active enzyme site active [23]. site [23]. Molecules 20192019,, 2424,, 1620x FOR PEER REVIEW 3 of 17 1.2. Coumarins 1.2. Coumarins Coumarins are natural products found in plants, fungi, and bacteria [32]. They are commonly foundCoumarins in food and are also natural widely products used in found cosmetics in plants, and fragrances fungi, and [33,34]. bacteria Coumarins [32]. They show are commonly a variety foundof biological in food activities, and also widelyincluding used anti-oxidant, in cosmetics an andti-cancer, fragrances anti-coagulant, [33,34]. Coumarins anti-inflammatory, show a variety anti- of biologicalfungal, anti-microbial, activities, including anti-viral, anti-oxidant, anti-neurodegenerative, anti-cancer, anti-coagulant, and anti-diabetic anti-inflammatory, activities anti-fungal, [32–34]. anti-microbial,Coumarin (2H-1-benzopyran-2-one) anti-viral, anti-neurodegenerative, backbone