Abstract: The actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the 'filagree' phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity) and 48 fascin-pathway enhancers (with potential cognitive-enhancer activity). The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure-activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the 'beads-on-a-string' defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery.
Abstract: Morolic (1) and moronic (2) acids are the main constituents of acetonic extract from Phoradendron reichenbachianum (Loranthaceae), a medicinal plant used in Mexico for the treatment of diabetes. The aim of the current study was to establish the sub-acute antidiabetic and antihyperlipidemic effects of compounds 1 and 2 over non insulin-dependent diabetic rat model. Also, to determine the antihyperglycemic action on normoglycemic rats by oral glucose tolerance test. Daily-administered morolic (1) and moronic (2) acids (50 mg/kg) significantly lowered the blood glucose levels at 60% since first day until tenth day after treatment than untreated group (p<0.05). Moreover, analyzed blood samples obtained from diabetic rats indicated that both compounds diminished plasmatic concentration of cholesterol (CHO) and triglycerides (TG), returning them to normal levels (p<0.05). Also, pretreatment with 50 mg/kg of each compound induced significant antihyperglycemic effect after glucose and sucrose loading (2 g/kg) compared with control group (p<0.05). In vitro studies showed that compounds 1 and 2 induced inhibition of 11β-HSD 1 activity at 10 μM. However, in silico analysis of the pentaclyclic triterpenic acids on 11β-HSD 1 revealed that all compounds had high docking scores and important interactions with the catalytic site allowing them to inhibit 11β-HSD 1 enzyme. In conclusion, morolic and moronic acids have shown sustained antidiabetic and antihyperglycemic action possibly mediated by an insulin sensitization with consequent changes of glucose, cholesterol and triglycerides, in part mediated by inhibition of 11β-HSD 1 as indicated by in vitro and in silico studies.
Abstract: A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR ((1)H, (13)C) spectroscopy, and single-crystal X-ray diffraction. The in vitro inhibitory activity of 1 against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated, showing a moderate inhibitory enzyme activity (51.17% of inhibition at 10 μM), being more active than clofibrate and clofibric acid. The antidiabetic activity of compound 1 was determined at 50 mg/Kg single dose using a non insulin dependent diabetes mellitus rat model. The results indicated a significant decrease of plasma glucose levels, during the 7h post-administration. Additionally, we performed a molecular docking of 1 into the ligand binding pocket of one subunit of human 11β-HSD1. In this model, compound 1 binds into the catalytic site of 11β-HSD1 in two different orientations. Both of them, show important short contacts with the catalytic residues Ser 170, Tyr 183, Asp 259 and also with the nicotinamide ring of NADP(+).
Abstract: Bioactive food compounds can be both therapeutically and nutritionally relevant. Screening strategies are widely employed to identify bioactive compounds from edible plants. Flavor additives contained in the so-called FEMA GRAS (generally recognized as safe) list of approved flavoring ingredients is an additional source of potentially bioactive compounds. This work used the principles of molecular similarity to identify compounds with potential mood-modulating properties. The ability of certain GRAS molecules to inhibit histone deacetylase-1 (HDAC1), proposed as an important player in mood modulation, was assayed. Two GRAS chemicals were identified as HDAC1 inhibitors in the micromolar range, results similar to what was observed for the structurally related mood prescription drug valproic acid. Additional studies on bioavailability, toxicity at higher concentrations, and off-target effects are warranted. The methodology described in this work could be employed to identify potentially bioactive flavor chemicals present in the FEMA GRAS list.
Abstract: Furin is the prototype member of the proprotein convertases superfamily. Proprotein convertases are associated with hormonal response, neural degeneration, viral and bacterial activation, and cancer. Several studies over the last decade have examined small molecules, natural products, peptides and peptide derivatives as furin inhibitors. Currently, subnanomolar inhibition of furin is possible. Herein, we report the analysis of 115 furin inhibitors reported in the literature. Analysis of the physicochemical properties of these compounds highlights the dependence of the inhibitory potency with the total formal charge and also shows how the most potent (peptide-based) furin inhibitors have physicochemical properties similar to drugs. In addition, we report docking studies of 26 furin inhibitors using Glide XP. Inspection of binding interactions shows that the two putative binding modes derived from our study are reasonable. Analysis of the binding modes and protein-ligand interaction fingerprints, used here as postdocking procedure, shows that electrostatic interactions predominate on S1, S2 and S4 subsites but are seldom in S3. Our models also show that the benzimidamide group, present in the most active inhibitors, can be accommodated in the S1 subsite. These results are valuable for the design of new furin inhibitors.
Abstract: The aim of the current study was to investigate the vasorelaxant activity of five structurally-related triterpenic acids namely ursolic (1), moronic (2), morolic (3), betulinic (4) and 3,4-seco-olean-18-ene-3,28-dioic (5) acids. The vasorelaxant effect of compounds 1-5 were determined on endothelium-denuded and endothelium-intact rat aortic rings pre-contracted with noradrenaline (0.1 μM). All compounds showed significant relaxant effect on endothelium-intact vessels in a concentration-dependent manner (p<0.05). Ursolic, moronic and betulinic acids were the most potent vasorelaxant agents with 11.7, 16.11 and 58.46 μM, respectively. Since vasorelaxation was blocked by L-NAME, while indomethacin did not inhibit the effect, endothelium-derived nitric oxide seems to be involved in triterpenic 2 and 3 mode of action. Compounds 1-5 were docked with a crystal structure of eNOS. Triterpenes 1-5 showed calculated affinity with eNOS in the C1 and C2 binding pockets, near the catalytic site; Ser248 and Asp480 are the residues that make hydrogen bonds with the triterpene compounds.
Abstract: Bacterial infections are becoming increasingly difficult to treat due to the development and spread of antibiotic resistance. Therefore, identifying novel antibacterial targets and new antibacterial agents capable of treating infections by drug-resistant bacteria is of vital importance. The structurally simple yet potent fusaricidin or LI-F class of natural products represents a particularly attractive source of candidates for the development of new antibacterial agents. We synthesized 18 fusaricidin/LI-F analogues and investigated the effects of structure modification on their conformation, serum stability, antibacterial activity, and toxicity toward human cells. Our findings show that substitution of an ester bond in depsipeptides with an amide bond may afford equally potent analogues with improved stability and greatly decreased cytotoxicity. The lower overall hydrophobicity/amphiphilicity of amide analogues in comparison with their parent depsipeptides, as indicated by HPLC retention times, may explain the dissociation of antibacterial activity and human cell cytotoxicity. These results indicate that amide analogues may have significant advantages over fusaricidin/LI-F natural products and their depsipeptide analogues as lead structures for the development of new antibacterial agents.
Abstract: Analysis of marketed drugs and commercial vendor libraries used in high-throughput screening suggests that the medicinally relevant chemical space may be expanded to unexplored regions. Novel regions of the chemical space can be conveniently explored with structurally unique molecules with increased complexity and balanced physicochemical properties. As a case study, we discuss the chemoinformatic profile of natural products in the Traditional Chinese Medicine (TCM) database and a large collection assembled from 30 small-molecule combinatorial libraries with emphasis on assessing molecular complexity. The herein surveyed combinatorial libraries have been successfully used over the past 20 years to identify novel bioactive compounds across different therapeutic areas. Combinatorial libraries and natural products are suitable sources to expand the traditional relevant medicinal chemistry space.
Abstract: The ethyl 2-(6-substituted benzo[d]thiazol-2-ylamino)-2-oxoacetate derivatives (OX 1-9) were prepared using a one-step reaction. The in vitro inhibitory activity of the compounds against protein tyrosine phosphatase 1B (PTP-1B) was evaluated. Compounds OX-(1, 6 and 7) were rapid reversible (mixed-type) inhibitors of PTP-1B with IC(50) values in the low micro-molar range. The most active compounds OX-(1, 6 and 7) were docked into the crystal structure of PTP-1B. Docking results indicate potential hydrogen bond interactions between the oxamate group in all compounds and the catalytic amino acid residues Arg221 and Ser216. The compounds were evaluated for their in vivo hypoglycemic activity, showing significant lowering of plasma glucose concentration in acute normoglycemic model and oral glucose tolerance test similarly at the effect exerted for hypoglycemic drug glibenclamide.
Abstract: Introduction: Despite the significant progress, research is still needed to reveal details of the complex and dynamic chemical processes operating in the central nervous system (CNS) and their relationship to psychological effects such as mood disorders. The incidence of behavioral depression is widely spread worldwide, with an estimated 14.8 million adults diagnosed yearly in the United States alone. The efficacy of current antidepressants on 50 - 60% of patients, their slow onset of action and the prevalence of adverse side effects highlight the need for developing a new generation of improved antidepressants. Computational methods have the potential to aid in the discovery of mood modulators. Areas covered: This review contains three main sections: historical evolution of marketed antidepressants, physicochemical and structural properties of antidepressant compounds reported in the ChEMBL database and recent efforts in the design and discovery of antidepressants using computational methods. The authors provide details of the computational methods employed, from chemoinformatic analyses to molecular modeling. Expert opinion: While there have been numerous and important findings in depression research, the high cost and time spent on research into new therapies for brain disorders is a risky undertaking. Computational methodologies can be employed to speed up the discovery of new antidepressants and to detect new sources of chemical compounds with potential antidepressant activity. Compound collections containing compounds already approved in the pharmaceutical and food industries that cover the property space and complement the structural space of CNS drugs represent a promising starting point for the discovery of new antidepressant agents.
Abstract: DNA methyltransferases (DNMTs) represent promising targets for the development of unique anticancer drugs. However, all DNMT inhibitors currently in clinical use are nonselective cytosine analogs with significant cytotoxic side-effects. Several natural products, covering diverse chemical classes, have indicated DNMT inhibitory activity, but these effects have yet to be systematically evaluated. In this study, we provide experimental data suggesting that two of the most prominent natural products associated with DNA methylation inhibition, (-)-epigallocathechin-3-gallate (EGCG) and curcumin, have little or no pharmacologically relevant inhibitory activity. We therefore conducted a virtual screen of a large database of natural products with a validated homology model of the catalytic domain of DNMT1. The virtual screening focused on a lead-like subset of the natural products docked with DNMT1, using three docking programs, following a multistep docking approach. Prior to docking, the lead-like subset was characterized in terms of chemical space coverage and scaffold content. Consensus hits with high predicted docking affinity for DNMT1 by all three docking programs were identified. One hit showed DNMT1 inhibitory activity in a previous study. The virtual screening hits were located within the biological-relevant chemical space of drugs, and represent potential unique DNMT inhibitors of natural origin. Validation of these virtual screening hits is warranted.
Abstract: The purpose of this work is to study the molecular association that occurs between 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 6-chloro-5-(1-naphthyloxy)-2-(trifluoromethyl)-1H-benzimidazole (RCB20), an antiparasitic compound recently found by our research group, with poor aqueous solubility. The complex stability constant and stoichiometric ratio determined by phase-solubility diagram and Job's plot provided evidence that HPβCD enhanced water solubility of RCB20 through inclusion complex formation. Two-dimensional ¹H NMR spectroscopy is used to study the molecular arrangement of inclusion complex in solution. These results are further supported using molecular modeling studies. In the solid state, the complexation is confirmed by differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy. Finally, RCB20/HPβCD complex has better activity than RCB20 against the adult and muscle larvae phase of Trichinella spiralis.
Abstract: Combinatorial libraries continue to play a key role in drug discovery. To increase structural diversity, several experimental methods have been developed. However, limited efforts have been performed so far to quantify the diversity of the broadly used diversity-oriented synthetic libraries. Herein, we report a comprehensive characterization of 15 bis-diazacyclic combinatorial libraries obtained through libraries from libraries, which is a diversity-oriented synthetic approach. Using MACCS keys, radial and different pharmacophoric fingerprints as well as six molecular properties, it was demonstrated the increased structural and property diversity of the libraries from libraries over the individual libraries. Comparison of the libraries to existing drugs, NCI diversity, and the Molecular Libraries Small Molecule Repository revealed the structural uniqueness of the combinatorial libraries (mean similarity < 0.5 for any fingerprint representation). In particular, bis-cyclic thiourea libraries were the most structurally dissimilar to drugs retaining drug-like character in property space. This study represents the first comprehensive quantification of the diversity of libraries from libraries providing a solid quantitative approach to compare and contrast the diversity of diversity-oriented synthetic libraries with existing drugs or any other compound collection.
Abstract: Parasitic infections caused by Entamoeba histolytica are still major threats against public health, especially in developing countries. Although current therapies exist, the problems associated with parasite resistance and negative side effects make it imperative to search for new therapeutic agents. A systematic scaffold analysis reported herein of a public database containing 474 antiamoebic compounds reveals that benzimidazole is the most active scaffold reported thus far. To gain insights into the antiamoebic activity of novel compounds, the authors report herein the biological activity of 12 compounds, including benzotriazole and indazole derivatives, scaffolds not previously tested against E. histolytica. Compounds with the benzotriazole and indazole scaffolds showed low micromolar activity (IC(50) = 0.304 and 0.339 mu M) and are more active than metronidazole, which is the drug of choice used for the treatment of amebiosis. The novel compounds have similar properties to approved drugs. Compounds with novel scaffolds represent promising starting points of an optimization program against E. histolytica. (Journal of Biomolecular Screening 2011;16:862-868)
Abstract: Introduction: Despite the significant progress, research is still needed to reveal details of the complex and dynamic chemical processes operating in the central nervous system (CNS) and their relationship to psychological effects such as mood disorders. The incidence of behavioral depression is widely spread worldwide, with an estimated 14.8 million adults diagnosed yearly in the United States alone. The efficacy of current antidepressants on 50 - 60% of patients, their slow onset of action and the prevalence of adverse side effects highlight the need for developing a new generation of improved antidepressants. Computational methods have the potential to aid in the discovery of mood modulators. Areas covered: This review contains three main sections: historical evolution of marketed antidepressants, physicochemical and structural properties of antidepressant compounds reported in the ChEMBL database and recent efforts in the design and discovery of antidepressants using computational methods. The authors provide details of the computational methods employed, from chemoinformatic analyses to molecular modeling. Expert opinion: While there have been numerous and important findings in depression research, the high cost and time spent on research into new therapies for brain disorders is a risky undertaking. Computational methodologies can be employed to speed up the discovery of new antidepressants and to detect new sources of chemical compounds with potential antidepressant activity. Compound collections containing compounds already approved in the pharmaceutical and food industries that cover the property space and complement the structural space of CNS drugs represent a promising starting point for the discovery of new antidepressant agents.
Abstract: A series of Î(2)-isoxazoline constrained analogues of procaine/procainamide (7a-k and 8a-k) were prepared and their inhibitory activity against DNA methyltransferase 1 (DNMT1) was tested. Among them, derivative 7b is far more potent in vitro (IC(50) = 150 μM) than other non-nucleoside inhibitors and also exhibits a strong and dose-dependent antiproliferative effect against HCT116 human colon carcinoma cells. The binding mode of 7b with the enzyme was also investigated by means of a simple competition assay as well as of docking simulations conducted using the recently published crystallographic structure of human DNMT1. On the basis of the findings, we assessed that the mode of inhibition of 7b is consistent with a competition with the cofactor and propose it as a novel lead compound for the development of non-nucleoside DNMT inhibitors.
Abstract: Parasitic infections caused by Entamoeba histolytica are still major threats against public health, especially in developing countries. Although current therapies exist, the problems associated with parasite resistance and negative side effects make it imperative to search for new therapeutic agents. A systematic scaffold analysis reported herein of a public database containing 474 antiamoebic compounds reveals that benzimidazole is the most active scaffold reported thus far. To gain insights into the antiamoebic activity of novel compounds, the authors report herein the biological activity of 12 compounds, including benzotriazole and indazole derivatives, scaffolds not previously tested against E. histolytica. Compounds with the benzotriazole and indazole scaffolds showed low micromolar activity (IC(50) = 0.304 and 0.339 µM) and are more active than metronidazole, which is the drug of choice used for the treatment of amebiosis. The novel compounds have similar properties to approved drugs. Compounds with novel scaffolds represent promising starting points of an optimization program against E. histolytica.
Abstract: A visualization plot of a data set of molecular data is a useful tool for gaining insight into a set of molecules. In chemoinformatics, most visualization plots are of molecular descriptors, and the statistical model most often used to produce a visualization is principal component analysis (PCA). This paper takes PCA, together with four other statistical models (NeuroScale, GTM, LTM, and LTM-LIN), and evaluates their ability to produce clustering in visualizations not of molecular descriptors but of molecular fingerprints. Two different tasks are addressed: understanding structural information (particularly combinatorial libraries) and relating structure to activity. The quality of the visualizations is compared both subjectively (by visual inspection) and objectively (with global distance comparisons and local k-nearest-neighbor predictors). On the data sets used to evaluate clustering by structure, LTM is found to perform significantly better than the other models. In particular, the clusters in LTM visualization space are consistent with the relationships between the core scaffolds that define the combinatorial sublibraries. On the data sets used to evaluate clustering by activity, LTM again gives the best performance but by a smaller margin. The results of this paper demonstrate the value of using both a nonlinear projection map and a Bernoulli noise model for modeling binary data.
Abstract: Combinatorial libraries continue to play a key role in drug discovery. To increase structural diversity, several experimental methods have been developed. However, limited efforts have been performed so far to quantify the diversity of the broadly used diversity-oriented synthetic libraries. Herein, we report a comprehensive characterization of 15 bis-diazacyclic combinatorial libraries obtained through libraries from libraries, which is a diversity-oriented synthetic approach. Using MACCS keys, radial and different pharmacophoric fingerprints as well as six molecular properties, it was demonstrated the increased structural and property diversity of the libraries from libraries over the individual libraries. Comparison of the libraries to existing drugs, NCI diversity, and the Molecular Libraries Small Molecule Repository revealed the structural uniqueness of the combinatorial libraries (mean similarity <0.5 for any fingerprint representation). In particular, bis-cyclic thiourea libraries were the most structurally dissimilar to drugs retaining drug-like character in property space. This study represents the first comprehensive quantification of the diversity of libraries from libraries providing a solid quantitative approach to compare and contrast the diversity of diversity-oriented synthetic libraries with existing drugs or any other compound collection.
Abstract: The aim of the current study was to investigate the oral antidiabetic activity of four structurally-related triterpenic acids: ursolic (RE-01), oleanolic (RE-02), moronic (RE-03) and morolic (RE-04) acids. STZ-nicotinamide diabetic rats were treated with these triterpenes (50 mg/kg) and the antidiabetic effects in acute experiment were determined. All compounds showed significant antidiabetic activity in comparison with control group (p<0.05). The in vitro inhibitory activity of compounds against protein tyrosine phosphatase 1B (PTP-1B) was also evaluated. At 50 μM, the enzymatic activity was almost completely inhibited. All compounds were docked with a crystal structure of PTP-1B. Docking results suggested the potential binding of the triterpenic acids in a binding pocket next to the catalytic site. An extensive hydrogen bond network with the carboxyl group and Van der Waals interactions stabilize the protein-ligand complexes.
Abstract: Virtual screening is increasingly being used in drug discovery programs with a growing number of successful applications. Experimental methodologies developed to speed up the drug discovery processes include high-throughput screening and combinatorial chemistry. The complementarities between computational and experimental screenings have been recognized and reviewed in the literature. Computational methods have also been used in the combinatorial chemistry field, in particular in library design. However, the integration of computational and combinatorial chemistry screenings has been attempted only recently. Combinatorial libraries (experimental or virtual) represent a notable source of chemically related compounds. Advances in combinatorial chemistry and deconvolution strategies, have enabled the rapid exploration of novel and dense regions in the chemical space. The present review is focused on the integration of virtual and experimental screening of combinatorial libraries. Applications of virtual screening to discover novel anticancer agents and our ongoing efforts towards the integration of virtual screening and combinatorial chemistry are also discussed.
Abstract: A protocol for stereochemical analysis, based on the systematic comparison between theoretical and experimental vicinal (1)H-(1)H NMR coupling constants, was developed and applied to a series of flexible compounds (1-8) derived from the 6-heptenyl-5,6-dihydro-2H-pyran-2-one framework. The method included a broad conformational search, followed by geometry optimization at the DFT B3LYP/DGDZVP level, calculation of the vibrational frequencies, thermochemical parameters, magnetic shielding tensors, and the total NMR spin-spin coupling constants. Three scaling factors, depending on the carbon atom hybridizations, were found for the (1)H-C-C-(1)H vicinal coupling constants: f((sp3)-(sp3)) = 0.910, f((sp3)-(sp2)) = 0.929, and f((sp2)-(sp2))= 0.977. A remarkable correlation between the theoretical (J(pre)) and experimental (1)H-(1)H NMR (J(exp)) coupling constants for spicigerolide (1), a cytotoxic natural product, and some of its synthetic stereoisomers (2-4) demonstrated the predictive value of this approach for the stereochemical assignment of highly flexible compounds containing multiple chiral centers. The stereochemistry of two natural 6-heptenyl-5,6-dihydro-2H-pyran-2-ones (14 and 15) containing diverse functional groups in the heptenyl side chain was also analyzed by application of this combined theoretical and experimental approach, confirming its reliability. Additionally, a geometrical analysis for the conformations of 1-8 revealed that weak hydrogen bonds substantially guide the conformational behavior of the tetraacyloxy-6-heptenyl-2H-pyran-2-ones.
Abstract: Protein kinase B (PKB/AKT) is an attractive therapeutic target in anticancer drug development. We have recently identified by docking-based virtual screening a low micromolar AKT-2 inhibitor. Additionally, the virtual screening hit represents a novel AKT-2 inhibitor scaffold. In this work, we discuss a structure-based design strategy toward the optimization of this hit. Following this strategy and using a herein validated docking protocol, we conducted the design of novel compounds with expected improved activity over the parent compound. The newly designed molecules have high predicted affinity for AKT-2; are synthetically accessible and are contained within the kinase-relevant property space.
Abstract: Comparative molecular field analysis (CoMFA) was performed on a set of IH-benzimidazole derivatives. Molecular modeling and 3D-QSAR were employed to determine the tautomeric form that would probably fit a target receptor in Entamoeba histolytica. CoMFA results suggest that the antiarnoebic activity is favored with steric bulk at position 5 of the benzimidazole ring and low electron density on the group at position 2. To the best of our knowledge this is the first 3D-QSAR study performed for benzimidazoles as antiamoebic agents. The CoMFA models derived will be very valuable to design new and more potent compounds against E histolytica. (c) 2006 Elsevier Ltd. All rights reserved.
Abstract: Docking experiments using a number of published crystal structures of HMG-CoA reductase with the potent hypocholesterolemic agent alpha-asarone are described. The results indicate that alpha-asarone binds in the enzyme's active site. The methoxy groups play a key role in the binding and probably also in its biological activity, as shown by extensive SAR studies reported for analogues of alpha-asarone. The docking results will be valuable for the structure-based design of novel hypolipidemic agents. (C) 2004 Elsevier Ltd. All rights reserved.
Abstract: The DNA methyltransferase (DNMT) enzyme family represents one of the most promising targets for the development of novel anticancer drugs. Using an homol. model of the catalytic domain of human DNMT1 we report herein mol. modeling studies of several small-mol. DNMT1 inhibitors including hydralazine, procaine, procainamide [Singh, N. et al.]. The docking models suggest key interactions between the inhibitors and the binding pocket that can be exploited in structure-based design. We also present our findings of docking-based virtual screening of large compd. databases for novel DNMT1 inhibitors.
