Prenylated flavonoids with significant anti-hepatoma activity from Daphne giraldii and effects on Fibroblast Growth Factor Receptor 1 (FGFR1).

We report here the orchestration of molecular ion networking (MoIN) and a set of computational and informatics assisted structural elucidation approaches in the discovery of 23 new prenyl-flavonoids and 13 known molecules from Daphne giraldii Nitsche (Thymelaeaceae), some of which possess significant bioactivity against hepatoma carcinoma. Daphnegiratriprenylone A (DPTP-A) represents the class of polyprenyl-flavonoids possessing a triprenyl substitution, and was identified with the guidance of mass spectrometry and nuclear magnetic resonance combined with computational approaches. This approach illustrates a paradigm shift in the application of computational tools for the direct assignment of new natural product structures and it was demonstrated to be reliable compared to conventional 2D-NMR techniques. Seventeen compounds exhibited potent and selective activity against Hep3B cells (IC50 ranging from 0.42 to 7.08 µM). Tyrosine kinase FGFR1 has emerged as a potential target of polyprenyl-flavonoids by a reverse pharmacophore mapping approach. We validated that the prenyl-flavonoids effectively inhibit FGFR1 using the Mobility Shift Assay, Western blot and molecular dynamics simulations, and the results suggest significant potency of the compounds towards FGFR1. These findings provide a new chemical class with strong links to traditional medicines, possessing reasonable safety for developing potential therapeutic agents for FGFR1-related diseases.

ROS-Responsive Glycopolymeric Nanoparticles for Enhanced Drug Delivery to Macrophages.

Macrophages play a diverse, key role in many pathologies, including inflammatory diseases, cardiovascular diseases, and cancer. However, many therapeutic strategies targeting macrophages suffer from systemic off-target toxicity resulting in notoriously narrow therapeutic windows. To address this shortcoming, the development of poly(propylene sulfide)-b-poly(methacrylamidoglucopyranose) [PPS-b-PMAG] diblock copolymer-based nanoparticles (PMAG NPs) capable of targeting macrophages and releasing drug in the presence of reactive oxygen species (ROS) is reported. PMAG NPs have desirable physicochemical properties for systemic drug delivery, including slightly negative surface charge, ≈100 nm diameter, and hemo-compatibility. Additionally, due to the presence of PPS in the NP core, PMAG NPs release drug cargo preferentially in the presence of ROS. Importantly, PMAG NPs display high cytocompatibility and are taken up by macrophages in cell culture at a rate ≈18-fold higher than PEGMA NPs-NPs composed of PPS-b-poly(oligoethylene glycol methacrylate). Computational studies indicate that PMAG NPs likely bind with glucose transporters such as GLUT 1/3 on the macrophage cell surface to facilitate high levels of internalization. Collectively, this study introduces glycopolymeric NPs that are uniquely capable of both receptor-ligand targeting to macrophages and ROS-dependent drug release and that can be useful in many immunotherapeutic settings.

Structure-based design of UDP-GlcNAc analogs as candidate GnT-V inhibitors.

BACKGROUND: N-Glycan branching regulates various functions of glycoproteins. N-Acetylglucosaminyltransferase V (GnT-V) is a GlcNAc transferase that acts on N-glycans and the GnT-V-producing branch is highly related to cancer progression. This indicates that specific GnT-V inhibitors may be drug candidates for cancer treatment. To design novel GnT-V inhibitors, we focused on the unique and weak recognition of the donor substrate UDP-GlcNAc by GnT-V. On the basis of the catalytic pocket structure, we hypothesized that UDP-GlcNAc analogs with increasing hydrophobicity may be GnT-V inhibitors. METHODS: We chemically synthesized 10 UDP-GlcNAc analogs in which one or two phosphate groups were replaced with hydrophobic groups. To test these compounds, we set up an HPLC-based enzyme assay system for all N-glycan-branching GlcNAc transferases in which GnT-I-V activity was measured using purified truncated enzymes. Using this system, we assessed the inhibitory effects of the synthesized compounds on GnT-V and their specificity. RESULTS: Several UDP-GlcNAc analogs inhibited GnT-V activity, although the inhibition potency was modest. Compared with other GnTs, these compounds showed a preference for GnT-V, which suggested that GnT-V was relatively tolerant of hydrophobicity in the donor substrate. Docking models of the inhibitory compounds with GnT-V suggested the mechanisms of how these compounds interacted with GnT-V and inhibited its action. CONCLUSIONS: Chemical modification of the donor substrate may be a promising strategy to develop selective inhibitors of GnT-V. GENERAL SIGNIFICANCE: Our findings provide new insights into the design of GnT inhibitors and how GnTs recognize the donor substrate.

Optimization of sulfobutyl-ether-ß-cyclodextrin levels in oral formulations to enhance progesterone bioavailability.

Progesterone oral dose regimens are indicated for the treatment of luteal phase deficiency and estrogen dominance. The poor aqueous solubility of progesterone leads to erratic oral absorption, resulting in suboptimal or excessive plasma levels. Developing a formulation to enhance the solubility of progesterone in the gastrointestinal tract would be beneficial to decrease drug absorption variability and increase bioavailability. The solubility of progesterone at 400 mM sulfobutyl-ether-ß-cyclodextrin (SBE-ß-CD) concentration was ~7000-fold greater than its intrinsic solubility, aided by the formation of SBE-ß-CD-progesterone complex. The complex was characterized using differential scanning colorimeter, Fourier-transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy techniques. FTIR and NMR studies of the complex confirm the interaction between functional groups of SBE-ß-CD and progesterone to form an inclusion complex. Molecular modeling studies demonstrated progesterone binding poses with four probable SBE-ß-CD isomers and these results matched with NMR and FTIR data. The progesterone oral formulations were optimized by increasing the levels of SBE-ß-CD in the formulation to prevent the displacement of progesterone from the complex by gastrointestinal contents. The oral bioavailability of progesterone in rats was increased 5-fold when administered with the optimized formulation compared to administration with progesterone API capsules. Studies demonstrated that the optimized formulation prevents precipitation of progesterone in the intestinal tract and increases progesterone oral bioavailability in rats.

Identification of a novel umami peptide in tempeh (Indonesian fermented soybean) and its binding mechanism to the umami receptor T1R.

Tempeh, a traditional Indonesian soybean product produced by fermentation, is especially popular because of its umami taste. In this study, a novel umami peptide GENEEEDSGAIVTVK (GK-15) was identified in the small peptide (<3 kDa) fraction of the water extract of tempeh using LC-MS/MS analysis and database-assisted identification. The umami taste of GK-15 was further validated using sensory evaluation, which suggested that GK-15 may be one of the key components contributing to the umami taste in tempeh. To rationalize the biological effect of GK-15, molecular docking of GK-15 into the N-terminal extracellular ligand-binding domain of the umami (T1R) receptor was performed. ZDOCK data showed that GK-15 could perfectly bind either to the open or closed conformation of T1R3. To the best of our knowledge, the present work is the first study to focus on the screening of umami peptides from tempeh.

Negative allosteric modulators of cannabinoid receptor 2: protein modeling, binding site identification and molecular dynamics simulations in the presence of an orthosteric agonist.

Selective activation of the cannabinoid receptor subtype 2 (CB2) shows promise for treating pain, inflammation, multiple sclerosis, cancer, ischemic/reperfusion injury and osteoporosis. Target selectivity and off-target side effects are two major limiting factors for orthosteric ligands, and therefore, the search for allosteric modulators (AMs) is a widely used drug discovery approach. To date, only a limited number of negative CB2 AMs have been identified, possessing only micromolar activity at best, and the CB2 receptor's allosteric site(s) are not well characterized. Herein, we used computational approaches including receptor modeling, site mapping, docking, molecular dynamics (MD) simulations and binding free energy calculations to predict, characterize and validate allosteric sites within the complex of the CB2 receptor with bound orthosteric agonist CP55,940. After docking of known negative CB2 allosteric modulators (NAMs), dihydro-gambogic acid (DHGA) and trans-ß-caryophyllene (TBC) (note that TBC also shows agonist activity), at the predicted allosteric sites, the best total complex with CB2, CP55,940 and NAM was embedded into a hydrated lipid bilayer and subjected to a 200 ns MD simulation. The presence of an AM affected the CB2-CP55,940 complex, altering the relative positioning of the toggle switch residues and promoting a strong π-π interaction between Phe1173.36 and Trp2586.48. Binding of either TBC or DHGA to a putative allosteric pocket directly adjacent to the orthosteric ligand reduced the binding free energy of CP55,940, which is consistent with the expected effect of a negative AM. The identified allosteric sites present immense scope for the discovery of novel classes of CB2 AMs.

Hepatoprotective Tetrahydrobenzocyclooctabenzofuranone Lignans from Kadsura longipedunculata.

Three new tetrahydrobenzocyclooctabenzofuranone lignan glucosides, longipedunculatins A-C (1-3), a new dibenzocyclooctadiene lignan glucoside, longipedunculatin D (4), a new dibenzocyclooctadiene lignan (5), five new tetrahydrobenzocyclooctabenzofuranone lignans (6-10), and two new simple lignans (11, 12) were isolated from the roots of Kadsura longipedunculata. Their structures and absolute configurations were established using a combination of MS, NMR, and experimental and calculated electronic circular dichroism data. Compound 7 showed moderate hepatoprotective activity against N-acetyl-p-aminophenol-induced toxicity in HepG2 cells with a cell survival rate at 10 µM of 50.8%. Compounds 2, 7, and 12 showed significant in vitro inhibitory effects with an inhibition rate of 55.1%, 74.9%, and 89.8% on nitric oxide production assays at 10 µM.

Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana).

The investigation of the constituents that were isolated from Turnera diffusa (damiana) for their inhibitory activities against recombinant human monoamine oxidases (MAO-A and MAO-B) in vitro identified acacetin 7-methyl ether as a potent selective inhibitor of MAO-B (IC50 = 198 nM). Acacetin 7-methyl ether (also known as 5-hydroxy-4', 7-dimethoxyflavone) is a naturally occurring flavone that is present in many plants and vegetables. Acacetin 7-methyl ether was four-fold less potent as an inhibitor of MAO-B when compared to acacetin (IC50 = 50 nM). However, acacetin 7-methyl ether was >500-fold selective against MAO-B over MAO-A as compared to only two-fold selectivity shown by acacetin. Even though the IC50 for inhibition of MAO-B by acacetin 7-methyl ether was ~four-fold higher than that of the standard drug deprenyl (i.e., SelegilineTM or ZelaparTM, a selective MAO-B inhibitor), acacetin 7-methyl ether's selectivity for MAO-B over MAO-A inhibition was greater than that of deprenyl (>500- vs. 450-fold). The binding of acacetin 7-methyl ether to MAO-B was reversible and time-independent, as revealed by enzyme-inhibitor complex equilibrium dialysis assays. The investigation on the enzyme inhibition-kinetics analysis with varying concentrations of acacetin 7-methyl ether and the substrate (kynuramine) suggested a competitive mechanism of inhibition of MAO-B by acacetin 7-methyl ether with Ki value of 45 nM. The docking scores and binding-free energies of acacetin 7-methyl ether to the X-ray crystal structures of MAO-A and MAO-B confirmed the selectivity of binding of this molecule to MAO-B over MAO-A. In addition, molecular dynamics results also revealed that acacetin 7-methyl ether formed a stable and strong complex with MAO-B. The selective inhibition of MAO-B suggests further investigations on acacetin 7-methyl as a potential new drug lead for the treatment of neurodegenerative disorders, including Parkinson's disease.

Computationally Assisted Discovery and Assignment of a Highly Strained and PANC-1 Selective Alkaloid from Alaska's Deep Ocean.

We report here the orchestration of molecular ion networking and a set of computationally assisted structural elucidation approaches in the discovery of a new class of pyrroloiminoquinone alkaloids that possess selective bioactivity against pancreatic cancer cell lines. Aleutianamine represents the first in a new class of pyrroloiminoquinone alkaloids possessing a highly strained multibridged ring system, discovered from Latrunculia ( Latrunculia) austini Samaai, Kelly & Gibbons, 2006 (class Demospongiae, order Poecilosclerida, family Latrunculiidae) recovered during a NOAA deep-water exploration of the Aleutian Islands. The molecule was identified with the guidance of mass spectrometry, nuclear magnetic resonance, and molecular ion networking (MoIN) analysis. The structure of aleutianamine was determined using extensive spectroscopic analysis in conjunction with computationally assisted quantifiable structure elucidation tools. Aleutianamine exhibited potent and selective cytotoxicity toward solid tumor cell lines including pancreatic cancer (PANC-1) with an IC50 of 25 nM and colon cancer (HCT-116) with an IC50 of 1 µM, and represents a potent and selective candidate for advanced preclinical studies.

Computationally Assisted Assignment of the Kadsuraols, a Class of Chemopreventive Agents for the Control of Liver Cancer.

Kadsuraols A-C (1-3), which are tetrahydrocyclobutaphenanthrofuranone-type lignans with a new carbon skeleton comprising a four-membered ring across C-1'-C-8, have been isolated from the roots of Kadsura longipedunculata. Their structures and absolute configurations were unambiguously determined using nuclear magnetic resonance, X-ray diffraction crystallography, DP4+ calculations, and computed and experimental electronic circular dichroism spectra. Kadsuraol C (3) exhibited hepatoprotective activity against N-acetyl- p-aminophenol (APAP)-induced toxicity. The compounds showed no cytotoxicity at 10 µM in a zone assay.

Interactions of endocannabinoid virodhamine and related analogs with human monoamine oxidase-A and -B.

The endocannabinoid system plays an important role in the pathophysiology of various neurological disorders, such as anxiety, depression, neurodegenerative diseases, and schizophrenia; however, little information is available on the coupling of the endocannabinoid system with the monoaminergic systems in the brain. In the present study, we tested four endocannabinoids and two anandamide analogs for inhibition of recombinant human MAO-A and -B (monoamine oxidase). Virodhamine inhibited both MAO-A and -B (IC50 values of 38.70 and 0.71 µM, respectively) with ∼55-fold greater inhibition of MAO-B. Two other endocannabinoids (noladin ether and anandamide) also showed good inhibition of MAO-B with IC50 values of 18.18 and 39.98 µM, respectively. Virodhamine was further evaluated for kinetic characteristics and mechanism of inhibition of human MAO-B. Virodhamine inhibited MAO-B (Ki value of 0.258 ±â€¯0.037 µM) through a mixed mechanism/irreversible binding and showed a time-dependent irreversible mechanism. Treatment of Neuroscreen-1 (NS-1) cells with virodhamine produced significant inhibition of MAO activity. This observation confirms potential uptake of virodhamine by neuronal cells. A molecular modeling study of virodhamine with MAO-B and its cofactor flavin adenine dinucleotide (FAD) predicted virodhamine's terminal -NH2 group to be positioned near the N5 position of FAD, but for docking to MAO-A, virodhamine's terminal -NH2 group was far away (∼6.52 Å) from the N5 position of FAD, and encountered bad contacts with nearby water molecules. This difference could explain virodhamine's higher potency and preference for MAO-B. The binding free energies for the computationally-predicted poses also showed that virodhamine was selective for MAO-B. These findings suggest potential therapeutic applications of virodhamine for the treatment of neurological disorders.

Hepatoprotective Dibenzocyclooctadiene and Tetrahydrobenzocyclooctabenzofuranone Lignans from Kadsura longipedunculata.

Five new dibenzocyclooctadiene lignans, longipedlignans A-E (1-5), five new tetrahydrobenzocyclooctabenzofuranones (6-10), and 18 known analogues (11-28) were isolated from the roots of Kadsura longipedunculata. Compounds 6-10 are new spirobenzofuranoid-dibenzocyclooctadiene-type lignans. Their structures and absolute configurations were established using a combination of MS, NMR, and electronic circular dichroism data. Spirobenzofuranoids 6 and 15 showed moderate hepatoprotective activity against N-acetyl- p-aminophenol-induced toxicity in HepG2 cells with cell survival rates at 10 µM of 52.2% and 50.2%, respectively.

Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds.

Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) click chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives. All the synthetic compounds were evaluated for their in vitro activity against chloroquine resistant Plasmodium falciparum (W2) and for cytotoxicity to HepG2 cells. Compounds containing the naphthoquinolyl triazole moieties showed higher antimalarial activity than lapachol (IC50 123.5 µM) and selectivity index (SI) values in the range of 4.5-197.7. Molecular docking simulations of lapachol, atovaquone and all the newly synthesized compounds were carried out for interactions with PfDHODH, a mitochondrial enzyme of the parasite respiratory chain that is essential for de novo pyrimidine biosynthesis. Docking of the naphthoquinonolyl triazole derivatives to PfDHODH yielded scores between -9.375 and -14.55 units, compared to -9.137 for lapachol and -12.95 for atovaquone and disclosed the derivative 17 as a lead compound. Therefore, the study results show the enhancement of DHODH binding affinity correlated with improvement of SI values and in vitro activities of the lapachol derivatives.

Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with elevated rates of mortality. Therapies to treat AKI are currently not available, so identification of new targets that can be modulated to ameliorate renal damage upon diagnosis of AKI is essential. In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295 [3'-methyl-4-(2-(thiophen-2-yl)propan-2-yl)biphenyl-2,6-diol], was designed, synthesized, and tested in vitro and in silico. Molecular docking of SMM-295 into a CB2 active-state homology model showed that SMM-295 interacts well with key amino acids to stabilize the active state. In human embryonic kidney 293 cells, SMM-295 was capable of reducing cAMP production with 66-fold selectivity for CB2 versus cannabinoid receptor 1 and dose-dependently increased mitogen-activated protein kinase and Akt phosphorylation. In vivo testing of the CB2 agonist was performed using a mouse model of bilateral IRI, which is a common model to mimic human AKI, where SMM-295 was immediately administered upon reperfusion of the kidneys after the ischemia episode. Histologic damage assessment 48 hours after reperfusion demonstrated reduced tubular damage in the presence of SMM-295. This was consistent with reduced plasma markers of renal dysfunction (i.e., creatinine and neutrophil gelatinase-associated lipocalin) in SMM-295-treated mice. Mechanistically, kidneys treated with SMM-295 were shown to have elevated activation of Akt with reduced terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL)-positive cells compared with vehicle-treated kidneys after IRI. These data suggest that selective CB2 receptor activation could be a potential therapeutic target in the treatment of AKI.

In silico investigation of lavandulyl flavonoids for the development of potent fatty acid synthase-inhibitory prototypes.

BACKGROUND: Inhibition of fatty acid synthase (FAS) is regarded as a sensible therapeutic strategy for the development of optimal anti-cancer agents. Flavonoids exhibit potent anti-neoplastic properties. METHODS: The MeOH extract of Sophora flavescens was subjected to chromatographic analyses such as VLC and HPLC for the purification of active flavonoids. The DP4 chemical-shift analysis protocol was employed to investigate the elusive chirality of the lavandulyl moiety of the purified polyphenols. Induced Fit docking protocols and per-residue analyses were utilized to scrutinize structural prerequisites for hampering FAS activity. The FAS-inhibitory activity of the purified flavonoids was assessed via the incorporation of [3H] acetyl-CoA into palmitate. RESULTS: Six flavonoids, including lavandulyl flavanones, were purified and evaluated for FAS inhibition. The lavandulyl flavanone sophoraflavanone G (2) exhibited the highest potency (IC50 of 6.7±0.2µM), which was more potent than the positive controls. Extensive molecular docking studies revealed the structural requirements for blocking FAS. Per-residue interaction analysis demonstrated that the lavandulyl functional group in the active flavonoids (1-3 and 5) significantly contributed to increasing their binding affinity towards the target enzyme. CONCLUSION: This research suggests a basis for the in silico design of a lavandulyl flavonoid-based architecture showing anti-cancer effects via enhancement of the binding potential to FAS. GENERAL SIGNIFICANCE: FAS inhibition by flavonoids and their derivatives may offer significant potential as an approach to lower the risk of various cancer diseases and related fatalities. In silico technologies with available FAS crystal structures may be of significant use in optimizing preliminary leads.

Screening, discovery, and characterization of angiotensin-I converting enzyme inhibitory peptides derived from proteolytic hydrolysate of bitter melon seed proteins.

In this study, new angiotensin-I converting enzyme (ACE) inhibitory peptides were comprehensively identified from a thermolysin digest of bitter melon (Momordica charantia) seed proteins. The hydrolysate was fractionated by reversed-phase high performance liquid chromatography (RP-HPLC), and the inhibitory activities of the resulting fractions were evaluated using ACE inhibitory assay. Two novel ACE inhibitory peptides (VY-7 and VG-8) were identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and database-assisted peptide sequencing. VY-7 and VG-8 were derived from momordin A and MAP30, respectively, and their IC50 values were as low as 8.64±0.60 and 13.30±0.62 µM, respectively. Lineweaver-Burk plots further indicated that VY-7, which showed the best IC50 value, acts as a competitive inhibitor. Notably, the content of VY-7 in crude thermolysin digest was determined to be as high as 14.89±0.88 µg/mg using LC-MS/MS quantification. In the spontaneously hypertensive rat (SHR) model, oral administration of VY-7 at 2mg/kg body weight significantly decreased the systolic blood pressure. The interaction between VY-7 and ACE was examined using molecular docking calculations and the results suggested that certain residues of VY-7 can fit perfectly into the S1, S1' and S2' regions of the binding pocket of ACE. BIOLOGICAL SIGNIFICANCE: One of the most common supportive therapies for treating hypertension is the use of synthetic drugs to inhibit ACE activity. Synthetic ACE inhibitors possess good antihypertensive effects, but come with accompanying side effects. Therefore, food-derived ACE inhibitory peptides are regarded as safer alternatives and are attracting much attention for hypertension treatment. In this study, we comprehensively identified peptides derived from bitter melon (Momordica charantia) seed proteins (BMSPs) using a shotgun proteomics approach. Based on results from an in vitro ACE inhibitory assay, two peptides (VY-7 and VG-8) derived from momordin A and MAP30 proteins, respectively, showed good ACE inhibitory activities. For VY-7, which showed the best IC50 value (8.64±0.60 µM), the inhibition type was determined to be competitive inhibition, as found using a Lineweaver-Burk plot. The novel ACE inhibitory peptide VY-7 (at 2mg/kg body weight) as well as the crude hydrolysate of BMSPs (at 10 mg/kg body weight) showed significant and moderate antihypertensive effects, respectively, in an animal model of hypertension, spontaneously hypertensive rats (SHRs). The present work demonstrated the screening of ACE inhibitory peptides from BMSPs and, as far as we know, VY-7 is the first well-characterized antihypertensive peptide derived from bitter melon seeds.

Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening.

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer's disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non-competitive CDK5/p25 inhibitors with good CDK2/E selectivity.

A novel natural phenyl alkene with cytotoxic activity.

A novel phenyl alkene (1) was isolated from a mixture of three Florida sponges, Smenospongia aurea, Smenospongia cerebriformis, and Verongula rigida. Unlike terpenoids or amino acid derivatives, which are commonly known classes of secondary metabolites from these genera, the chemical structure of 1 showed an unprecedented linear phenyl alkene skeleton. Through comprehensive analyses of NMR and MS data, the gross structure of 1 was determined to be (E)-10-benzyl-5,7-dimethylundeca-1,5,10-trien-4-ol. The absolute configuration at C-4 was established as R by a modified Mosher's method. Based on the relative configuration between C-4 and C-7, the absolute configuration at C-7 was assigned as S. Compound 1 showed in vitro cytotoxic activity against HL-60 human leukemia cancer cells with an IC50 value of 8.1 µM. Molecular docking study suggests that the structure of compound 1 matches the pharmacophore of eribulin required to display cytotoxic activity through the inhibition of microtubule activity.

Quantitative structure-activity relationships of imidazole-containing farnesyltransferase inhibitors using different chemometric methods.

Farnesyltranseferase inhibitors (FTIs) are one of the most promising classes of anticancer agents, but though some compounds in this category are in clinical trials there are no marketed drugs in this class yet. Quantitative structure activity relationship (QSAR) models can be used for predicting the activity of FTI candidates in early stages of drug discovery. In this study 192 imidazole-containing FTIs were obtained from the literature, structures of the molecules were optimized using Hyperchem software, and molecular descriptors were calculated using Dragon software. The most suitable descriptors were selected using genetic algorithms-partial least squares (GA-PLS) and stepwise regression, and indicated that the volume, shape and polarity of the FTIs are important for their activities. 2D-QSAR models were prepared using both linear methods, i.e., multiple linear regression (MLR), and non-linear methods, i.e., artificial neural networks (ANN) and support vector machines (SVM). The proposed QSAR models were validated using internal and external validation methods. The results show that the proposed 2D-QSAR models are valid and that they can be applied to predict the activities of imidazole-containing FTIs. The prediction capability of the 2D-QSAR (linear and non-linear) models is comparable to and somewhat better than that of previous 3D-QSAR models and the non-linear models are more accurate than the linear models.

Combined rule extraction and feature elimination in supervised classification.

There are a vast number of biology related research problems involving a combination of multiple sources of data to achieve a better understanding of the underlying problems. It is important to select and interpret the most important information from these sources. Thus it will be beneficial to have a good algorithm to simultaneously extract rules and select features for better interpretation of the predictive model. We propose an efficient algorithm, Combined Rule Extraction and Feature Elimination (CRF), based on 1-norm regularized random forests. CRF simultaneously extracts a small number of rules generated by random forests and selects important features. We applied CRF to several drug activity prediction and microarray data sets. CRF is capable of producing performance comparable with state-of-the-art prediction algorithms using a small number of decision rules. Some of the decision rules are biologically significant.