Structure-Based Drug Design for Cytochrome P450 Family 1 Inhibitors

Table 1

The summary of studies on CYP1-ligand interactions.

Cytochrome P450	Ligand	Methods	Notes	References
CYP1A1 and other cytochromes
CYP1A1 and CYP1A2	Aromatic amines, heterocyclic amines, aromatic hydrocarbons (benzo(a)pyrenemethylcholantrene), phenacetin, furafylline, and 7-methoxyresorufin	Homology modeling based on the CYP102 crystal structure	Human, mouse, rabbit, and trout CYP sequences	[22]
CYP1A1	7-Ethoxyresorufin, 7-methoxyresorufin, and benzo[a]pyrene	Homology modeling		[28]
CYP1A1, CYP1A2, and CYP1B1	Rutaecarpine and its derivatives	Homology modeling		[29]
CYP1A1	Arachidonic acid and eicosopentaenoic acid	Homology modeling	Molecular docking explains regiospecificity of metabolism	[30]
CYP1A1 and CYP1A2	7-Methoxyresorufin and 7-ethoxyresorufin	Homology modeling	Active site mutations in human CYP1A1 and CYP1A2	[31]
CYP1A1 and CYP1A2	Dietary flavonoids	Homology modeling		[32]
CYP1A1	B[a]P, B[a]P-7R, 8R-dihydrodiol, B[a]P-7S, 8S-dihydrodiol, eicosapentaenoate, and arachidonate	Homology modeling	Regioselectivity	[33]
CYP1A1	Ethoxyresorufin	Homology modeling		[34]
CYP1A1	B[a]P	Wild-type and exon 6 del CYP1A1 homology models		[35]
CYP1A1, CYP1A2, and CYP1B1	Alkoxyl derivatives of 7,8-dehydrorutaecarpine	Homology models based on the crystal structure of rabbit CYP2C5		[36]
CYP1A1	B[a]P, TCB, and TCDD	Rat, human, scup, and killifish homology models		[37]
CYP1A1	Representative ligands: α-naphthoflavone and benzothiazole	Homology modeling		[38]
CYP1A1 and CYP1A2 (CYP2A6 and CYP2B1)	Arylacetylenes	CYP1A2 crystal structure (PDB: 2HI4) and homology model of CYP1A1	Distances of ligands to heme, Fe, and Phe residues were analyzed	[39]
CYP1A1	Benzoxazoles and benzothiazoles	CoMFA, homology modeling, and molecular docking		[40]
CYP1A1, CYP1A2, and CYP1B1 (CYP2C9 and CYP3A4)	33 flavonoid derivatives	PDB: 2HI4 and homology models of CYP1A1 and CYP1B1	Hydroxyl and methoxy derivatives of flavone more potent as CYP inhibitors	[41]
CYP1A1, CYP1A2, and CYP1B1	Methoxyflavonoids	PDB: 2HI4 and homology models of CYP1A1 and CYP1B1	Important amino acid residues	[42]
CYP1A1 and CYP2B1	p-Aminophenol-succinic acid derivatives (acetylcholinesterase inhibitors)	Homology modeling of rat CYPs based on structures of CYP1A2 and CYP3A4 and molecular dynamics	Biological experiments on rat microsomes induced with 5,6-benzoflavone and phenobarbital	[43]
CYP1A1, CYP1A2, and CYP1B1	17-β-Estradiol	PDB: 2HI4 and homology models of CYP1A1 and CYP1B1	Important amino acid residues	[44]
CYP1A1	3,3′,4,4′,5-Pentachlorobiphenyl	Homology modeling	Rat and human recombinant microsomes	[45]
CYP1A1 and CYP1B1	Resveratrol and its derivatives	Homology modeling based on CYP1A2 crystal structure		[46]
CYP1A1 and CYP1B1	Dietary flavonoids	Homology models based on the structure of CYP1A2 (PDB: 2HI4)		[47]
CYP1A1 and CYP1A2 (CYP1A6 and CYP2B1)	Flavone propargyl ethers	CYP1A2 crystal structure (PDB: 2HI4) and homology model of CYP1A1	Flavone propargyl ethers are more potent inhibitors of CYP1A1 and CYP1A2 than the parent hydroxy flavones	[48]
CYP1A1 and CYP1A2	Phenacetin and acetaminophen	CYP1A2 crystal structure (PDB: 2HI4) and homology model of CYP1A1	Isoform-selective metabolism	[49]
CYP1A1 and CYP1B1	Polycyclic aromatic hydrocarbons	Homology modeling		[50]
CYP1A1	Sulforaphane	The tertiary structure of CYP1A1 was generated with the combination methods of threading, ab initio modeling, and structural refinement	Sulforaphane failed to reduce the genotoxic effect of TCDD in yeast cells	[51]
CYP1A1	Pyrimidobenzothiazole (NSC745689)	Homology modeling and molecular dynamics		[52]
CYP1A1, CYP1A2, and CYP1B1 (CYP2A6 and CYP2B1)	Pyranoflavones		Molecular surface images generated from UCSF Chimera	[53]
CYP1A1 and CYP1A2	Ethynylflavones	PDB: 4I8V and PDB: 2HI4	Selective inhibitory activity toward CYP1A1	[54]
CYP1A1	Polychlorinated dibenzo-p-dioxins and coplanar polychlorinated biphenyls	Homology modeling	Rat and human CYP1A1	[55]
CYP1A1, CYP1A2, and CYP1B1	Polymethoxystilbenes	PDB: 4I8V, PDB: 2HI4, and PDB: 3PM0	Potent and selective inhibitory activity of 2,3′,4′-trimethoxy-trans-stilbene	[56]
CYP1A1, CYP1A2, and CYP1B1	30 drugs metabolized by CYPs	PDB: 4I8V, PDB: 2HI4, and PDB: 3PM0	MetaSite	[57]
CYP1A1 and CYP1A2	22 aromatic hydrocarbons and 3 fluorogenic alkoxyaryl compounds	PDB: 4I8V and PDB: 2HI4	CYP1A variants	[58]
CYP1A1, CYP1A2, and CYP1B1	Alkoxyresorufins	Homology modeling	Baikal seal and human CYPs	[59]
CYP1A1, CYP1A2, and CYP1B1	5F-203, 5-aminoflavone, 17-β-estradiol, melatonin, debrisoquine, theophylline, clozapine, and lidocaine	PDB: 4I8V, PDB: 2HI4, and PDB: 3PM0	Differences in substrate specificity among CYPs	[60]
CYP1A1	Naringenin and dihydroxybergamottin	Rat homology model, human PDB: 4I8V, and molecular dynamics		[61]
CYP1A1	Compounds selected by virtual screening of databases	Database screening, Hypo1; metabolite prediction study, MetaSite software; molecular docking studies; and molecular dynamics simulations	Antiproliferative activity on MDA-MB-435 human cells and two lead compounds with antitumor activity against MDA-MB-435 line	[62]
CYP1A1, CYP1A2, and CYP1B1	Polymethoxy- and methylthio-trans-stilbene derivatives	PDB: 4I8V, PDB: 2HI4, and PDB: 3PM0		[63]
CYP1A2 and other cytochromes
CYP1A2	Caffeine and MeIQ	Homology model based on CYP BM3 crystal structure		[64]
CYP1A2 (CYP2D6 and CYP3A4)	Selected substrates	Homology modeling	Substrate selectivity studies	[65]
CYP1A2	7-Methoxyresorufin	Homology model based on the crystal structure of CYP2C5	Hydrogen bonds and π-π stacking with Phe226	[66]
CYP1A2 (CYP2A6, CYP2C9, CYP3A4, and CYP2E1)	Caffeine, theophylline, acetanilide, phenacetin, 7-methoxycoumarin, 7-ethoxycoumarin, 3-cyano-7′-ethoxycoumarin, naproxen, tacrine, amitriptyline, clozapine, and 7-ethoxyresorufin	PDB: 2HI4	Regioselectivity prediction of CYP1A2-mediated metabolism	[67]
CYP1A2	Methoxyresorufin and ethoxyresorufin	CYP1A2 homology model and crystal structure PDB: 2HI4 and homology structures of CYP1A2 mutants		[68]
CYP1A2	Virtual screening of CYP1A2 ligands	PDB: 2HI4 and automated docking (Gold version 3.2)	Prediction of the site of metabolism	[69]
CYP1A2	Structurally diverse CYP1A2 ligands (substrates and inhibitors)	PDB: 2HI4 and molecular dynamics	Versatility and plasticity of the CYP1A2 active site	[70]
CYP1A2 (CYP2C9)	Chrysin, 7,8-benzoflavone, 7-hydroxyflavone, and warfarin	PDB: 2HI4 and molecular dynamics		[71]
CYP1A2	Phenacetin	PDB: 2HI4	Wild-type and mutant forms of enzyme	[72]
CYP1A2	Virtual screening of 971 herb compounds	Pharmacophore searching and docking procedure to CYP1A2 crystal structure (PDB: 2HI4)	Herb-drug interactions	[73]
CYP1A2 (CYP2A6, CYP2C9, and CYP2D6)		PDB: 2HI4 and molecular dynamics	Flexibility at normal and high-pressure conditions (300 MPa)	[74]
CYP1A2 and CYP1B1	Polymethoxy-trans-stilbenes	PDB: 2HI4 and homology model of CYP1B1	Potent and selective inhibitory activity of 2,4,2′,6′-tetramethoxy-trans-stilbene	[75]
CYP1A2	7,8-Benzoflavone, oroxylin, and wogonin	PDB: 2HI4, binding free energy analysis with the MM-PBSL method, and molecular dynamics		[76]
CYP1A2 and CYP1B1	4′-Methylthio-trans-stilbene derivatives	PDB: 2HI4 and PDB: 3PM0		[77]
CYP1A2	7-Ethoxyresorufin	PDB: 2HI4, ensemble docking, and molecular dynamics	Phe186Leu mutation	[78]
CYP1A2 (CYP2C9, CYP2D6, and CYP3A4)	Kinase inhibitors	PDB: 2HI4	Drug-drug interactions	[79]
CYP1A2 (CYP2A6, CYP2C9, CYP3A4, and CYP2E1)	Acetaminophen	Large-scale 2D umbrella sampling, PDB: 2HI4, and molecular dynamics	Regioselectivity	[80]
CYP1A2		The initial structure of wild-type CYP1A2 (CYP1A2.1) constructed from the CYP1A2 crystal structure PDB: 2HI4, and CYP1A2 mutants constructed from CYP1A2.1 refined after molecular dynamics simulation	Influence of amino acid mutations on the 3D structure and dynamic properties of the enzyme	[81]
CYP1B1
CYP1B1	17-β-Estradiol, α-naphthoflavone, 7-ethoxycoumarin, 7-ethoxyresorufin, bufuralol, and benzo(a)pyrene-7,8-diol	Homology model based on the structure of CYP2C5	Allelic variant effects on metabolism	[82]
CYP1B1	17-β-Estradiol	Molecular dynamics simulations of homology-modeled structures	PCG-associated mutants	[83]
CYP1B1	7,8-Benzoflavone derivatives	PDB: 3PM0; MOE docking program	Inhibitors that eliminate CYP1B1-mediated drug resistance	[16]

B[a]P: benzo[a]pyrene; TCB: 2,3′,4,4′-tetrachlorobiphenyl; TCDD: tetrachlorodibenzo-p-dioxin; PCG: primary congenital glaucoma.