Publications by authors named "Robert J Doerksen"

80 Publications

Enantioselective Interactions of Anti-Infective 8-Aminoquinoline Therapeutics with Human Monoamine Oxidases A and B.

Pharmaceuticals (Basel) 2021 Apr 22;14(5). Epub 2021 Apr 22.

Division of Drug Discovery, Department of Infectious Diseases, Southern Research, Birmingham, AL 35205, USA.

8-Aminoquinolines (8-AQs) are an important class of anti-infective therapeutics. The monoamine oxidases (MAOs) play a key role in metabolism of 8-AQs. A major role for MAO-A in metabolism of primaquine (PQ), the prototypical 8-AQ antimalarial, has been demonstrated. These investigations were further extended to characterize the enantioselective interactions of PQ and NPC1161 (8-[(4-amino-1-methylbutyl) amino]-5-[3, 4-dichlorophenoxy]-6-methoxy-4-methylquinoline) with human MAO-A and -B. NPC1161B, the ()-(-) enantiomer with outstanding potential for malaria radical cure, treatment of visceral leishmaniasis and pneumocystis pneumonia infections is poised for clinical development. PQ showed moderate inhibition of human MAO-A and -B. Racemic PQ and ()-(-)-PQ both showed marginally greater (1.2- and 1.6-fold, respectively) inhibition of MAO-A as compared to MAO-B. However, ()-(+)-PQ showed a reverse selectivity with greater inhibition of MAO-B than MAO-A. Racemic NPC1161 was a strong inhibitor of MAOs with 3.7-fold selectivity against MAO-B compared to MAO-A. The ()-(+) enantiomer (NPC1161A) was a better inhibitor of MAO-A and -B compared to the ()-(-) enantiomer (NPC1161B), with more than 10-fold selectivity for inhibition of MAO-B over MAO-A. The enantioselective interaction of NPC1161 and strong binding of NPC1161A with MAO-B was further confirmed by enzyme-inhibitor binding and computational docking analyses. Differential interactions of PQ and NPC1161 enantiomers with human MAOs may contribute to the enantioselective pharmacodynamics and toxicity of anti-infective 8-AQs therapeutics.
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http://dx.doi.org/10.3390/ph14050398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146505PMC
April 2021

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

Int J Pharm 2021 Mar 23;596:120212. Epub 2021 Jan 23.

Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS 38677, USA; Institute for Drug Delivery and Biomedical Research, Bangalore, India. Electronic address:

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-β-cyclodextrin (SBE-β-CD) concentration was ~7000-fold greater than its intrinsic solubility, aided by the formation of SBE-β-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-β-CD and progesterone to form an inclusion complex. Molecular modeling studies demonstrated progesterone binding poses with four probable SBE-β-CD isomers and these results matched with NMR and FTIR data. The progesterone oral formulations were optimized by increasing the levels of SBE-β-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.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120212DOI Listing
March 2021

Negative allosteric modulators of cannabinoid receptor 1: Ternary complexes including CB1, orthosteric CP55940 and allosteric ORG27569.

J Biomol Struct Dyn 2021 Jan 22:1-19. Epub 2021 Jan 22.

Department of BioMolecular Sciences, Division of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS, USA.

In October 2019, the first X-ray crystal structure of a ternary cannabinoid receptor 1 (CB1) complex (PDB ID: 6KQI) was published, including the well-known orthosteric agonist, CP55940, and the well-studied negative allosteric modulator, ORG27569. Prior to the release of 6KQI, we applied binding pocket analysis and molecular docking to carefully prepared computational models of the ternary CB1 complex, in order to predict the binding site for ORG27569 with the CP55940-bound CB1 receptor. We carefully studied the binding pose of agonist ligands in the CB1 orthosteric pocket, including CP55940. Our computational studies identified the most favorable binding site for ORG27569, in the CP55940-CB1 complex, to be at the intracellular end of the receptor. However, in the 6KQI structure, ORG27569 was found at an extrahelical, intramembrane site on the complex, a site that partially overlaps with the site predicted in our calculations to be second-best. We performed molecular dynamics simulations of the CP55940-bound CB1 complex with ORG27569 at different binding sites. Our analysis of the simulations indicated that ORG27569 bound favorably and stably in each simulation, but, as in the earlier calculations, bound best at the intracellular site, which is different than that found in the crystal structure. These results suggest that the intracellular site might serve as an alternative binding site in CB1. Our studies show that the computational techniques we used are valuable in identifying ligand-binding pockets in proteins, and could be useful for the study of the interaction mode of other allosteric modulators.
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http://dx.doi.org/10.1080/07391102.2021.1873187DOI Listing
January 2021

Identification of potential non-nucleoside MraY inhibitors for tuberculosis chemotherapy using structure-based virtual screening.

J Biomol Struct Dyn 2020 Dec 22:1-18. Epub 2020 Dec 22.

Department of BioMolecular Sciences, Division of Medicinal Chemistry, University of Mississippi, University, MS, USA.

The efforts to limit the spread of the tuberculosis epidemic have been challenged by the rise of drug-resistant strains of (), the causative agent of tuberculosis. It is critical to discover new chemical scaffolds acting on novel or unexploited targets to beat this drug-resistant pathogen. MraY (phospho-MurNAc-pentapeptide translocase or translocase I) is an validated target for antibacterials-discovery. MraY is inhibited by nucleoside-based natural products that suffer from poor efficacy. The current study is focused on discovering novel chemical entities, particularly, non-nucleoside small molecules, as MraY inhibitors possessing antituberculosis activity. In the absence of any reported X-ray crystal structures of MraY, we used a homology model-based virtual screening approach combined with the ligand-based e-pharmacophore screening. We screened ∼12 million commercially available compounds from the ZINC15 database using GOLD software. The resulting hits were filtered using a 2-pronged screening method comprising e-pharmacophore hypotheses and docking against the MraY homology model using Glide. Further clustering based on Glide scores and optimal binding interactions resulted in 15 hits. We performed molecular dynamics (MD) simulations for the three best-ranking compounds and one other poorer-ranking compound, out of the 15 hits, to analyze the interaction modes in detail. The MD simulations indicated stable interactions between the compounds and key residues in the MraY active site that are crucial for maintaining the enzymatic activity. These hits could advance the antibacterial drug discovery campaign to find new MraY inhibitors for tuberculosis treatment.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1862705DOI Listing
December 2020

Selective Interactions of -Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B.

Molecules 2020 Nov 17;25(22). Epub 2020 Nov 17.

Department of Infectious Diseases, Division of Drug Discovery, Southern Research, Birmingham, AL 35205, USA.

A set of structurally related -methylated flavonoid natural products isolated from (), ( and ), (), (), and () plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds , , and showed selective inhibition of MAO-A, while and showed selective inhibition of MAO-B. Compound showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds - and with MAO-A, and compounds and with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by and , while a partially-reversible mixed-type inhibition by . Similarly, enzyme inhibition-kinetics analysis with compounds , , and , suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the -methylated flavonoids ( and -) and chalcones ( and ) to MAO-A matched closely with the trend in the experimental ICs. Analysis of the binding free-energies suggested better interaction of and with MAO-B than with MAO-A. The natural -methylated flavonoid () with highly potent inhibition (IC 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.
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http://dx.doi.org/10.3390/molecules25225358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697615PMC
November 2020

Potential Modulation of Human NAD[P]H-Quinone Oxidoreductase 1 (NQO1) by EGCG and Its Metabolites-A Systematic Computational Study.

Chem Res Toxicol 2020 11 2;33(11):2749-2764. Epub 2020 Nov 2.

Division of Hepatology, Albert Einstein Medical Center, Philadelphia, Pennsylvania 19141, United States.

At high doses, green tea extracts and green tea's major active constituent, (-)-epigallocatechin gallate (EGCG), despite their generally perceived health benefits, have been suspected to cause hepatotoxicity in certain human populations. It has been reported that -quinone metabolites of gallic acid or EGCG are causative agents for this hepatotoxicity. However, no experimental information is available at the molecular level on the possible role of NQO1 in the detoxification of EGCG and its metabolites, including reactive intermediates. In the present study, we investigated the possibility of NQO1 inhibition by EGCG and its metabolites by studying their interaction profiles and binding mechanism at the active site of NQO1 using molecular docking, binding free energy calculations, and molecular dynamics (MD) simulations. The binding free energy calculations showed that some metabolites exhibited strong predicted binding affinity and found that the binding orientation of the EGCG metabolites overlapped with that of dicoumarol found in an NQO1 X-ray crystal structure. The results suggest that these metabolites may act as strong NQO1 inhibitors, highlighting the need for experimental validation of this with appropriate biological methods. The Prime MM-GBSA computed average binding free energies after MD simulations of compounds , , , , and revealed that these compounds highly favored van der Waals (VdW) and Coulombic interactions with NQO1. In addition, the MD results revealed that selected EGCG metabolites formed a stable and strong complex with NQO1, with amino acids W105, Y126, Y128, H161, F178, H194, F232, and F236 being critical for potential NQO1 binding. The current results together with experimental data as well as studies of the polymorphisms of NQO1 (especially C609T) may explain the observed idiosyncratic hepatotoxicity caused by the consumption of green tea and its constituents.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00450DOI Listing
November 2020

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

Food Chem 2020 Dec 4;333:127411. Epub 2020 Jul 4.

Department of Biological Science and Technology, National Pingtung University of Science and Technology, 1 Shuefu Road, Neipu, Pingtung 91201, Taiwan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.foodchem.2020.127411DOI Listing
December 2020

Hypervalent Iodine Mediated Oxidative Cyclization of Acrylamide -Carbamates to 5,5-Disubstituted Oxazolidine-2,4-diones.

J Org Chem 2020 06 11;85(11):7549-7557. Epub 2020 May 11.

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Health Building 2, Room 7036, Houston, Texas 77204-5000, United States.

A metal-free oxidative cyclization of -Boc-acrylamides with (diacetoxyiodo)benzene in acetic acid produced 5,5-disubstituted oxazolidine-2,4-diones with the formation of a C-O bond in moderate to excellent yields. In addition, the reaction was diastereospecific with -Boc-2,3-dimethylacrylamides and proceeded with phenyl migration in the case of an -Boc-2-phenylacrylamide to generate a 5-acetoxy-5-benzyloxazolidine-2,4-dione.
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http://dx.doi.org/10.1021/acs.joc.0c00581DOI Listing
June 2020

Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease.

Eur J Med Chem 2020 Jul 10;198:112257. Epub 2020 Apr 10.

Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India. Electronic address:

In our overall goal to overcome the limitations associated with natural products for the management of Alzheimer's disease and to develop in-vivo active multifunctional cholinergic inhibitors, we embarked on the development of ferulic acid analogs. A systematic SAR study to improve upon the cholinesterase inhibition of ferulic acid with analogs that also had lower logP was carried out. Enzyme inhibition and kinetic studies identified compound 7a as a lead molecule with preferential acetylcholinesterase inhibition (AChE IC = 5.74 ± 0.13 μM; BChE IC = 14.05 ± 0.10 μM) compared to the parent molecule ferulic acid (% inhibition of AChE and BChE at 20 μM, 15.19 ± 0.59 and 19.73 ± 0.91, respectively). Molecular docking and dynamics studies revealed that 7a fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Asp74, Trp286, and Tyr337 in AChE and with Tyr128, Trp231, Leu286, Ala328, Phe329, and Tyr341 in BChE. Compound 7a was found to be an efficacious antioxidant in a DPPH assay (IC = 57.35 ± 0.27 μM), and it also was able to chelate iron. Data from atomic force microscopy images demonstrated that 7a was able to modulate aggregation of amyloid β. Upon oral administration, 7a exhibited promising in-vivo activity in the scopolamine-induced AD animal model and was able to improve spatial memory in cognitive deficit mice in the Y-maze model. Analog 7a could effectively reverse the increased levels of AChE and BChE in scopolamine-treated animals and exhibited potent ex-vivo antioxidant properties. These findings suggest that 7a can act as a lead molecule for the development of naturally-inspired multifunctional molecules for the management of Alzheimer's and other neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.ejmech.2020.112257DOI Listing
July 2020

Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway.

mSphere 2020 01 8;5(1). Epub 2020 Jan 8.

National Center for Natural Products Research, School of Pharmacy, University of Mississippi, Oxford, Mississippi, USA

The cell wall-targeting echinocandin antifungals, although potent and well tolerated, are inadequate in treating fungal infections due to their narrow spectrum of activity and their propensity to induce pathogen resistance. A promising strategy to overcome these drawbacks is to combine echinocandins with a molecule that improves their activity and also disrupts drug adaptation pathways. In this study, we show that puupehenone (PUUP), a marine-sponge-derived sesquiterpene quinone, potentiates the echinocandin drug caspofungin (CAS) in CAS-resistant fungal pathogens. We have conducted RNA sequencing (RNA-seq) analysis, followed by genetic and molecular studies, to elucidate PUUP's CAS-potentiating mechanism. We found that the combination of CAS and PUUP blocked the induction of CAS-responding genes required for the adaptation to cell wall stress through the cell wall integrity (CWI) pathway. Further analysis showed that PUUP inhibited the activation of Slt2 (Mpk1), the terminal mitogen-activated protein (MAP) kinase in this pathway. We also found that PUUP induced heat shock response genes and inhibited the activity of heat shock protein 90 (Hsp90). Molecular docking studies predicted that PUUP occupies a binding site on Hsp90 required for the interaction between Hsp90 and its cochaperone Cdc37. Thus, we show that PUUP potentiates CAS activity by a previously undescribed mechanism which involves a disruption of Hsp90 activity and the CWI pathway. Given the requirement of the Hsp90-Cdc37 complex in Slt2 activation, we suggest that inhibitors of this complex would disrupt the CWI pathway and synergize with echinocandins. Therefore, the identification of PUUP's CAS-potentiating mechanism has important implications in the development of new antifungal combination therapies. Fungal infections cause more fatalities worldwide each year than malaria or tuberculosis. Currently available antifungal drugs have various limitations, including host toxicity, narrow spectrum of activity, and pathogen resistance. Combining these drugs with small molecules that can overcome these limitations is a useful strategy for extending their clinical use. We have investigated the molecular mechanism by which a marine-derived compound potentiates the activity of the antifungal echinocandin caspofungin. Our findings revealed a mechanism, different from previously reported caspofungin potentiators, in which potentiation is achieved by the disruption of Hsp90 activity and signaling through the cell wall integrity pathway, processes that play important roles in the adaptation to caspofungin in fungal pathogens. Given the importance of stress adaptation in the development of echinocandin resistance, this work will serve as a starting point in the development of new combination therapies that will likely be more effective and less prone to pathogen resistance.
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http://dx.doi.org/10.1128/mSphere.00818-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952202PMC
January 2020

Conformational properties of l-fucose and the tetrasaccharide building block of the sulfated l-fucan from Lytechinus variegatus.

J Struct Biol 2020 01 4;209(1):107407. Epub 2019 Nov 4.

Institute of Medical Biochemistry Leopoldo de Meis, University Hospital Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941, RJ, Brazil; BioMolecular Sciences Department, School of Pharmacy, University of Mississippi, University, 38677 MS, USA; Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, 38677 MS, USA. Electronic address:

Although the 3D structure of carbohydrates is known to contribute to their biological roles, conformational studies of sugars are challenging because their chains are flexible in solution and consequently the number of 3D structural restraints is limited. Here, we investigate the conformational properties of the tetrasaccharide building block of the Lytechinus variegatus sulfated fucan composed of the following structure [l-Fucp4(SO)-α(1-3)-l-Fucp2,4(SO)-α(1-3)-l-Fucp2(SO)-α(1-3)-l-Fucp2(SO)] and the composing monosaccharide unit Fucp, primarily by nuclear magnetic resonance (NMR) experiments performed at very low temperatures and using HO as the solvent for the sugars rather than using the conventional deuterium oxide. By slowing down the fast chemical exchange rates and forcing the protonation of labile sites, we increased the number of through-space H-H distances that could be measured by NMR spectroscopy. Following this strategy, additional conformational details of the tetrasaccharide and l-Fucp in solution were obtained. Computational molecular dynamics was performed to complement and validate the NMR-based measurements. A model of the NMR-restrained 3D structure is offered for the tetrasaccharide.
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http://dx.doi.org/10.1016/j.jsb.2019.107407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810140PMC
January 2020

Hepatoprotective Tetrahydrobenzocyclooctabenzofuranone Lignans from .

J Nat Prod 2019 10 26;82(10):2842-2851. Epub 2019 Sep 26.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica , Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , People's Republic of China.

Three new tetrahydrobenzocyclooctabenzofuranone lignan glucosides, longipedunculatins A-C (-), a new dibenzocyclooctadiene lignan glucoside, longipedunculatin D (), a new dibenzocyclooctadiene lignan (), five new tetrahydrobenzocyclooctabenzofuranone lignans (-), and two new simple lignans (, ) were isolated from the roots of Their structures and absolute configurations were established using a combination of MS, NMR, and experimental and calculated electronic circular dichroism data. Compound showed moderate hepatoprotective activity against -acetyl--aminophenol-induced toxicity in HepG2 cells with a cell survival rate at 10 μM of 50.8%. Compounds , , and 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.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00576DOI Listing
October 2019

Salvindolin elicits opioid system-mediated antinociceptive and antidepressant-like activities.

J Psychopharmacol 2019 07 13;33(7):865-881. Epub 2019 Jun 13.

5 Department of Pharmacology, Federal University of Goiás, Goiânia, Brazil.

Background: Salvinorin A is known as a highly selective kappa opioid receptor agonist with antinociceptive but mostly pro-depressive effects.

Aims: In this article, we present its new semisynthetic analog with preferential mu opioid affinity, and promising antinociceptive, as well as antidepressant-like activities.

Methods: Competitive binding studies were performed for salvindolin with kappa opioid and mu opioid. The mouse model of nociception (acetic-acid-induced writhing, formalin, and hot plate tests), depression (forced swim and tail suspension tests), and the open field test, were used to evaluate antinociceptive, antidepressant-like, and locomotion effects, respectively, of salvindolin. We built a 3-D molecular model of the kappa opioid receptor, using a mu opioid X-ray crystal structure as a template, and docked salvindolin into the two proteins.

Results/outcomes: Salvindolin showed affinity towards kappa opioid and mu opioid receptors but with 100-fold mu opioid preference. Tests of salvindolin in mice revealed good oral bioavailability, antinociceptive, and antidepressive-like effects, without locomotor incoordination. Docking of salvindolin showed strong interactions with the mu opioid receptor which matched well with experimental binding data. Salvindolin-induced behavioral changes in the hot plate and forced swim tests were attenuated by naloxone (nonselective opioid receptor antagonist) and/or naloxonazine (selective mu opioid receptor antagonist) but not by nor-binaltorphimine (selective kappa opioid receptor antagonist). In addition, WAY100635 (a selective serotonin 1A receptor antagonist) blocked the antidepressant-like effect of salvindolin.

Conclusions/interpretation: By simple chemical modification, we were able to modulate the pharmacological profile of salvinorin A, a highly selective kappa opioid receptor agonist, to salvindolin, a ligand with preferential mu opioid receptor affinity and activity on the serotonin 1A receptor. With its significant antinociceptive and antidepressive-like activities, salvindolin has the potential to be an analgesic and/or antidepressant drug candidate.
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http://dx.doi.org/10.1177/0269881119849821DOI Listing
July 2019

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

Molecules 2019 Feb 23;24(4). Epub 2019 Feb 23.

National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA.

The investigation of the constituents that were isolated from (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 (IC = 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 (IC = 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 IC for inhibition of MAO-B by acacetin 7-methyl ether was ~four-fold higher than that of the standard drug deprenyl (i.e., Selegiline or Zelapar, 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.
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http://dx.doi.org/10.3390/molecules24040810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412401PMC
February 2019

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

J Am Chem Soc 2019 03 5;141(10):4338-4344. Epub 2019 Mar 5.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy , Medical University of South Carolina , Charleston , South Carolina 29425 , United States.

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 IC of 25 nM and colon cancer (HCT-116) with an IC of 1 μM, and represents a potent and selective candidate for advanced preclinical studies.
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http://dx.doi.org/10.1021/jacs.8b11403DOI Listing
March 2019

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

J Biomol Struct Dyn 2020 01 5;38(1):32-47. Epub 2019 Feb 5.

Department of BioMolecular Sciences, Division of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS, USA.

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 -β-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 Phe117 and Trp258. 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.
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http://dx.doi.org/10.1080/07391102.2019.1567384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487276PMC
January 2020

Structure-Based Identification of Potent Natural Product Chemotypes as Cannabinoid Receptor 1 Inverse Agonists.

Molecules 2018 Oct 13;23(10). Epub 2018 Oct 13.

Department of BioMolecular Sciences, Division of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, MS 38677, USA.

Natural products are an abundant source of potential drugs, and their diversity makes them a rich and viable prospective source of bioactive cannabinoid ligands. Cannabinoid receptor 1 (CB1) antagonists are clinically established and well documented as potential therapeutics for treating obesity, obesity-related cardiometabolic disorders, pain, and drug/substance abuse, but their associated CNS-mediated adverse effects hinder the development of potential new drugs and no such drug is currently on the market. This limitation amplifies the need for new agents with reduced or no CNS-mediated side effects. We are interested in the discovery of new natural product chemotypes as CB1 antagonists, which may serve as good starting points for further optimization towards the development of CB1 therapeutics. In search of new chemotypes as CB1 antagonists, we screened the in silico purchasable natural products subset of the ZINC12 database against our reported CB1 receptor model using the structure-based virtual screening (SBVS) approach. A total of 18 out of 192 top-scoring virtual hits, selected based on structural diversity and key protein⁻ligand interactions, were purchased and subjected to in vitro screening in competitive radioligand binding assays. The in vitro screening yielded seven compounds exhibiting >50% displacement at 10 μM concentration, and further binding affinity (K and IC) and functional data revealed compound as a potent and selective CB1 inverse agonist (K = 121 nM and EC = 128 nM) while three other compounds-, , and -were potent but nonselective CB1 ligands with low micromolar binding affinity (K). In order to explore the structure⁻activity relationship for compound , we further purchased compounds with >80% similarity to compound , screened them for CB1 and CB2 activities, and found two potent compounds with sub-micromolar activities. Most importantly, these bioactive compounds represent structurally new natural product chemotypes in the area of cannabinoid research and could be considered for further structural optimization as CB1 ligands.
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http://dx.doi.org/10.3390/molecules23102630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222380PMC
October 2018

Antileishmanial Carbasugars from Geosmithia langdonii.

J Nat Prod 2018 10 9;81(10):2222-2227. Epub 2018 Oct 9.

Assiut University Mycological Center, Assiut University , Assiut 71515 , Egypt.

Two new carbasugar-type metabolites, (1 S,2 R,3 R,4 R,5 R)-2,3,4-trihydroxy-5-methylcyclohexyl-2',5'-dihydroxybenzoate (1) and (1 S,2 S,3 S,4 R,5 R)-4-[(2',5'-dihydroxybenzyl)oxy]-5-methylcyclohexane-1,2,3-triol (2), were isolated from the filamentous fungus Geosmithia langdonii isolated from cotton textiles from Assiut, Egypt. The structures of 1 and 2 were elucidated based on comprehensive 1D and 2D NMR and MS data. Compounds 1 and 2 showed antileishmanial activity against Leishmania donovani with IC values of 100 and 57 μM, respectively. The (1 S,2 R,3 R,4 R,5 R) absolute configuration of carbasugar 1 was assigned via 2D NMR and experimental and calculated electronic circular dichroism (ECD) data. Similarly, the tentative structure of compound 2 was shown to possess a (1 S,2 S,3 S,4 R,5 R) absolute configuration via comparing its experimental ECD data and the specific rotation with 1 as well as examining the energy-minimized 3D computational models of compounds 1 and 2.
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http://dx.doi.org/10.1021/acs.jnatprod.8b00473DOI Listing
October 2018

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

Org Lett 2018 09 7;20(18):5559-5563. Epub 2018 Sep 7.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy , Medical University of South Carolina , Charleston , South Carolina 29425 , United States.

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.
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http://dx.doi.org/10.1021/acs.orglett.8b02207DOI Listing
September 2018

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

Biochem Pharmacol 2018 09 26;155:82-91. Epub 2018 Jun 26.

Department of BioMolecular Sciences and National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, United States; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, United States. Electronic address:

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 (IC 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 IC 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 (K value of 0.258 ± 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 -NH group to be positioned near the N5 position of FAD, but for docking to MAO-A, virodhamine's terminal -NH 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.
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http://dx.doi.org/10.1016/j.bcp.2018.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298601PMC
September 2018

Agonists of the γ-aminobutyric acid type B (GABA) receptor derived from β-hydroxy and β-amino difluoromethyl ketones.

Bioorg Med Chem Lett 2018 09 7;28(16):2697-2700. Epub 2018 Apr 7.

Department of BioMolecular Sciences, University of Mississippi, University, MS 38677, United States. Electronic address:

β-Hydroxy difluoromethyl ketones represent the newest class of agonists of the GABA-B receptor, and they are structurally distinct from all other known agonists at this receptor because they do not display the carboxylic acid or amino group of γ-aminobutyric acid (GABA). In this report, the design, synthesis, and biological evaluation of additional analogues of β-hydroxy difluoromethyl ketones characterized the critical nature of the substituted aromatic group on the lead compound. The importance of these new data is interpreted by docking studies using the X-ray structure of the GABA-B receptor. Moreover, we also report that the synthesis and biological evaluation of β-amino difluoromethyl ketones provided the most potent compound across these two series.
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http://dx.doi.org/10.1016/j.bmcl.2018.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152937PMC
September 2018

Hepatoprotective Dibenzocyclooctadiene and Tetrahydrobenzocyclooctabenzofuranone Lignans from Kadsura longipedunculata.

J Nat Prod 2018 04 29;81(4):846-857. Epub 2018 Mar 29.

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , People's Republic of China.

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.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00934DOI Listing
April 2018

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

Eur J Med Chem 2018 Feb 24;145:191-205. Epub 2017 Dec 24.

Pontifícia Universidade Católica de Minas Gerais, PUC Minas, Departamento de Física e Química, Instituto de Ciências Exatas e Informática ICEI, Av. Dom José Gaspar, 500 Prédio 34 Coração Eucarístico, CEP 30535.901, Belo Horizonte, MG, Brazil; Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, UFMG, Av. Antônio Carlos, 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil. Electronic address:

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 (IC 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.
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http://dx.doi.org/10.1016/j.ejmech.2017.12.051DOI Listing
February 2018

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

J Pharmacol Exp Ther 2018 02 29;364(2):287-299. Epub 2017 Nov 29.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (J.D.P., S.M.M., A.A., S.A., B.M.M., F.P.); Division of Medicinal Chemistry, Department of Biomolecular Sciences (P.P., K.K.R., R.J.D.) and Research Institute of Pharmaceutical Sciences (R.J.D.), School of Pharmacy, University of Mississippi, University, Mississippi; and National Institute of Pharmaceutical Education and Research, Jadavpur, Kolkata, West Bengal, India (K.K.R.)

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.
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http://dx.doi.org/10.1124/jpet.117.245522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774215PMC
February 2018

Assignment of the absolute configuration of hepatoprotective highly oxygenated triterpenoids using X-ray, ECD, NMR J-based configurational analysis and HSQC overlay experiments.

Biochim Biophys Acta Gen Subj 2017 Dec 15;1861(12):3089-3095. Epub 2017 Sep 15.

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, United States. Electronic address:

Background: The plants of the genus Kadsura are widely distributed in China, South Korea, and Japan. Their roots and stems are traditionally used to treat blood diseases and pain. The main bioactive constituents of Kadsura longipedunculata comprise highly oxygenated triterpenoids. Schiartane-type nortriterpenoids showed anti-HIV, anti-HBV, and cytotoxic bioactivities. For such compounds, the absolute configuration influences the bioactivities, and hence its unambiguous determination is essential. In this work, the absolute configurations of three highly oxygenated schiartane-type nortriterpenoids were unequivocally assigned using X-ray, ECD, and J-based configuration analysis and HSQC overlay data.

Methods: The ethanol extract of Kadsura longipedunculata Finet et Gagnep was purified by column chromatography using silica, Sephadex LH-20, and ODS as substrates. To help assign the absolute configuration of schiartane-type nortriterpenoids, X-ray diffraction analysis, ECD experiment compared to ab initio computed data, DP4+ analysis, HSQC overlay, NOESY, and J-based configuration analysis were carried out. Hetero- and homo-nuclear coupling constants were extracted from HETLOC experiments.

Results: Three new highly oxygenated triterpenoids, micrandilactone I (1), micrandilactone J (2), and 22,23-di-epi-micrandilactone J (3) were isolated. Their 2D structures were solved using NMR and HRESIMS data and their absolute configurations were elucidated using X-ray diffraction analysis, ECD experimental results compared to ab initio computed spectra, HSQC overlay, DP4+, NOESY, and J-based configuration analysis. Micrandilactone I (1) and 22,23-di-epi-micrandilactone J (3) showed moderate hepatoprotective activity against APAP-induced toxicity in HepG2 cells with cell survival rates of 53.0 and 50.2%, respectively, at 10μM (bicyclol, 49.0%), while micrandilactone J (2) was inactive.

General Significance: This is the first comprehensive stereochemical assignment of a non-crystalline schiartane-type nortriterpenoid like 3. This general protocol may contribute towards solving the problems hampering the assignment of the absolute configurations of other members of this class of nortriterpenoids.
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http://dx.doi.org/10.1016/j.bbagen.2017.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053918PMC
December 2017

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

Biochim Biophys Acta Gen Subj 2017 Jan 13;1861(1 Pt A):3180-3188. Epub 2016 Aug 13.

College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea. Electronic address:

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 [H] 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 (IC 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.
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http://dx.doi.org/10.1016/j.bbagen.2016.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918680PMC
January 2017

Methemoglobinemia Hemotoxicity of Some Antimalarial 8-Aminoquinoline Analogues and Their Hydroxylated Derivatives: Density Functional Theory Computation of Ionization Potentials.

Chem Res Toxicol 2016 07 1;29(7):1132-41. Epub 2016 Jul 1.

National Center for Natural Products Research, Research Institute of Pharmaceutical Science, and ‡Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi , University, Mississippi 38677, United States.

The administration of primaquine (PQ), an essential drug for the treatment and radical cure of malaria, can lead to methemoglobin formation and life-threatening hemolysis for glucose-6-phosphate dehydrogenase deficient patients. The ionization potential (IP, a quantitative measure of the ability to lose an electron) of the metabolites generated by antimalarial 8-aminoquinoline (8-AQ) drugs like PQ has been believed to be correlated in part to this methemoglobinemia hemotoxicity: the lower the IP of an 8-AQ derivative, the higher the concentration of methemoglobin generated. In this work, demethoxylated primaquine (AQ02) was employed as a model, by intensive computation at the B3LYP-SCRF(PCM)/6-311++G**//B3LYP/6-31G** level in water, to study the effects of hydroxylation at various positions on the ionization potential. Compared to the parent AQ02, the IPs of AQ02's metabolites hydroxylated at N1', C5, and C7 were lower by 61, 30, and 19 kJ/mol, respectively, while differences in the IP relative to PQ were small for hydroxylation at all other positions. The C6 position, at which the IP of the hydroxylated metabolite was greater than that of AQ02, by 2 kJ/mol, was found to be unique. Several literature and proposed 8-AQ analogues were studied to evaluate substituent effects on their potential to generate methemoglobin, with the finding that hydroxylations at N1' and C5 contribute the most to the potential hemotoxicity of PQ-based antimalarials, whereas hydroxylation at C7 has little effect. Phenoxylation at C5 in PQ-based 8-AQs can block the hydroxylation at C5 and reduce the potential for methemoglobin generation, while -CF3 and chlorines attached to the phenolic ring can further reduce the risk. The H-shift at N1' during the cationization of hydroxylated metabolites of 8-AQs sharply decreased their IPs, but this effect can be significantly reduced by the introduction of an electron-withdrawing group to the quinoline core. The results and this approach may be utilized for the design of safer antimalarial 8-AQ analogues.
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http://dx.doi.org/10.1021/acs.chemrestox.6b00063DOI Listing
July 2016

Data in support of optimized production of angiotensin-I converting enzyme inhibitory peptides derived from proteolytic hydrolysate of bitter melon seed proteins.

Data Brief 2015 Dec 9;5:403-7. Epub 2015 Oct 9.

Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; Research Center for Tropic Agriculture, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; Research Center for Austronesian Medicine and Agriculture, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan.

VY-7 has been demonstrated as a potent ACE inhibitory peptide in the previous study [1]. In this article, we provide accompanying data about the identification of bitter melon seed proteins (BMSPs), and quantitative analysis and optimized production of VY-7 in BMSPs hydrolysate.
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http://dx.doi.org/10.1016/j.dib.2015.09.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773410PMC
December 2015

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

J Proteomics 2015 Oct 3;128:424-35. Epub 2015 Sep 3.

Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; Research Center for Tropic Agriculture, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; Research Center for Austronesian Medicine and Agriculture, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan. Electronic address:

Unlabelled: 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.
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http://dx.doi.org/10.1016/j.jprot.2015.08.018DOI Listing
October 2015

Nitroreductase-triggered activation of a novel caged fluorescent probe obtained from methylene blue.

Chem Commun (Camb) 2015 Aug;51(64):12787-90

Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.

A near-infrared fluorescent probe based on methylene blue (p-NBMB) was developed for the detection of nitroreductase. Conjugating methylene blue with a p-nitrobenzyl moiety enables it to be activated by nitroreductase-catalyzed 1,6-elimination, resulting in the release of an active methylene blue fluorophore.
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http://dx.doi.org/10.1039/c5cc03824cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547460PMC
August 2015
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