- In 2008, I got the opportunity to continue my academic education at the University of Innsbruck in the field of compu... moreIn 2008, I got the opportunity to continue my academic education at the University of Innsbruck in the field of computational chemistry / molecular modeling. At that time, pharmacophore modeling as well as molecular docking were integral parts of my molecular modeling studies, and these studies frequently included virtual screening campaigns. In 2016, in addition to docking studies molecular dynamics (MD) simulations were conducted in a case, wherer it was of special concern, and yielded a more differentiated view on ligand protein-binding and interaction mechanisms.edit
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Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) possesses anti-inflammatory and anti-carcinogenic properties in vivo, and these features have been related to interference with multiple targets including XIAPs, NFκB, STAT-3, Akt and... more
Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) possesses anti-inflammatory and anti-carcinogenic properties in vivo, and these features have been related to interference with multiple targets including XIAPs, NFκB, STAT-3, Akt and mTOR. However, interference with these proteins requires relatively high concentrations of embelin (IC₅₀>4 μM) and cannot fully explain its bioactivity observed in several functional studies. Here we reveal human 5-lipoxygenase (5-LO) and microsomal prostaglandin E₂ synthase (mPGES)-1 as direct molecular targets of embelin. Thus, embelin potently suppressed the biosynthesis of eicosanoids by selective inhibition of 5-LO and mPGES-1 with IC₅₀=0.06 and 0.2 μM, respectively. In intact human polymorphonuclear leukocytes and monocytes, embelin consistently blocked the biosynthesis of various 5-LO products regardless of the stimulus (fMLP or A23187) with IC₅₀=0.8-2 μM. Neither the related human 12- and 15-LO nor the cyclooxygenases-1 and -2 or cytosolic phospholipase A₂ were significantly affected by 10 μM embelin. Inhibition of 5-LO and mPGES-1 by embelin was (I) essentially reversible after wash-out, (II) not impaired at higher substrate concentrations, (III) unaffected by inclusion of Triton X-100, and (IV) did not correlate to its proposed antioxidant properties. Docking simulations suggest concrete binding poses in the active sites of both 5-LO and mPGES-1. Because 5-LO- and mPGES-1-derived eicosanoids play roles in inflammation and cancer, the interference of embelin with these enzymes may contribute to its biological effects and suggests embelin as novel chemotype for development of dual 5-LO/mPGES-1 inhibitors.
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The microsomal prostaglandin E2 synthase (mPGES)-1 is the terminal enzyme in the biosynthesis of prostaglandin (PG)E2 from cyclooxygenase (COX)-derived PGH2. We previously found that mPGES-1 is inhibited by boswellic acids (IC50 = 3-30... more
The microsomal prostaglandin E2 synthase (mPGES)-1 is the terminal enzyme in the biosynthesis of prostaglandin (PG)E2 from cyclooxygenase (COX)-derived PGH2. We previously found that mPGES-1 is inhibited by boswellic acids (IC50 = 3-30 μM), which are bioactive triterpene acids present in the anti-inflammatory remedy frankincense. Here we show that besides boswellic acids, additional known triterpene acids (i.e., tircuallic, lupeolic, and roburic acids) isolated from frankincense suppress mPGES-1 with increased potencies. In particular, 3α-acetoxy-8,24-dienetirucallic acid (6) and 3α-acetoxy-7,24-dienetirucallic acid (10) inhibited mPGES-1 activity in a cell-free assay with IC50 = 0.4 μM, each. Structure-activity relationship studies and docking simulations revealed concrete structure-related interactions with mPGES-1 and its cosubstrate glutathione. COX-1 and -2 were hardly affected by the triterpene acids (IC50 > 10 μM). Given the crucial role of mPGES-1 in inflammation and the ...
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The microsomal prostaglandin E2 synthase (mPGES)-1 is the terminal enzyme in the biosynthesis of prostaglandin (PG)E2 from cyclooxygenase (COX)-derived PGH2. We previously found that mPGES-1 is inhibited by boswellic acids (IC50 = 3−30... more
The microsomal prostaglandin E2 synthase (mPGES)-1 is the terminal enzyme in the biosynthesis of prostaglandin (PG)E2 from cyclooxygenase (COX)-derived PGH2. We previously found that mPGES-1 is inhibited by boswellic acids (IC50 = 3−30 μM), which are bioactive triterpene acids present in the anti-inflammatory remedy frankincense. Here we show that besides boswellic acids, additional known triterpene acids (i.e., tircuallic, lupeolic, and roburic acids) isolated from frankincense suppress mPGES-1 with increased potencies. In particular, 3α-acetoxy-8,24dienetirucallic acid (6) and 3α-acetoxy-7,24-dienetirucallic acid (10) inhibited mPGES-1 activity in a cell-free assay with IC50 = 0.4 μM, each. Structure−activity relationship studies and docking simulations revealed concrete structure-related interactions with mPGES-1 and its cosubstrate glutathione. COX-1 and-2 were hardly affected by the triterpene acids (IC50 > 10 μM). Given the crucial role of mPGES-1 in inflammation and the abundance of highly active triterpene acids in frankincence extracts, our findings provide further evidence of the anti-inflammatory potential of frankincense preparations and reveal novel, potent bioactivities of tirucallic acids, roburic acids, and lupeolic acids.
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Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led... more
Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure-activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14-oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicat...
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Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led... more
Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure−activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the μ-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/μ-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5α-epoxy group, along with the tendency to affect the 3−7 lock switch. The emerged SARs reveal the subtle interplay between the substituents at positions 5 and 14 in the morphinan scaffold by enabling the identification of key structural elements that determine the distinct pharmacological profiles. This study provides a significant structural basis for understanding ligand binding and μ-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design.
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Position 6 of the morphinan skeleton plays a key role in the μ-opioid receptor (MOR) activity in vitro and in vivo. We describe the consequence of the 6-carbonyl group deletion in N-methylmorphinan-6-ones 1−4 on ligand−MOR interaction,... more
Position 6 of the morphinan skeleton plays a key role in the μ-opioid receptor (MOR) activity in vitro and in vivo. We describe the consequence of the 6-carbonyl group deletion in N-methylmorphinan-6-ones 1−4 on ligand−MOR interaction, signaling, and antinociception. While 6-desoxo compounds 1a, 2a, and 4a show similar profiles to their 6-keto counterparts, the 6-desoxo-14-benzyloxy substituted 3a displays significantly increased MOR binding and agonist potency and a distinct binding mode compared with its analogue 3.
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Research Interests: Biochemistry, Chemistry, Organic Chemistry, Medicinal Chemistry, Medicine, and 15 moreMolecular, Cell line, Humans, Quantitative Structure Activity Relationship, Enzyme, Medicinal, Carboxylic Acids, Imidazoles, Cell free System, Protein Binding, Chemical Synthesis, Cell Survival, Pharmacophore, binding sites, and Pharmacology and pharmaceutical sciences
ABSTRACT: Microsomal prostaglandin E 2 synthase-1 (mPGES-1) catalyzes prostaglandin E2 formation and is considered as a potential anti-inflammatory pharmacological target. To identify novel chemical scaffolds active on this enzyme, two... more
ABSTRACT: Microsomal prostaglandin E 2 synthase-1 (mPGES-1) catalyzes prostaglandin E2 formation and is considered as a potential anti-inflammatory pharmacological target. To identify novel chemical scaffolds active on this enzyme, two pharmacophore models for acidic mPGES-1 inhibitors were developed and theoretically validated using information on mPGES-1 inhibitors from literature. The models were used to screen chemical databases supplied from the National Cancer Institute (NCI) and the Specs. Out of 29 compounds selected for biological evaluation, nine chemically diverse compounds caused concentration-dependent inhibition of mPGES-1 activity in a cell-free assay with IC 50 values between 0.4 and 7.9 μM, respectively. Further pharmacological characterization revealed that also 5-lipoxygenase (5-LO) was inhibited by most of these active compounds in cell-free and cell-based assays with IC50 values in the low micromolar range. Together, nine novel chemical scaffolds inhibiting mPGE...
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Research Interests: Chemistry, Organic Chemistry, Modeling, Medicine, Embryo, and 15 moreCell line, Humans, Computer Simulation, Molecular Model, Bioorganic and medicinal Chemistry, Recombinant Proteins, Enzymatic Activity, Ligand, Adamantane, Ligands, Pharmacophore, Protein Kinase Inhibitors, nuclear factor kappa B, binding sites, and Pharmacology and pharmaceutical sciences
Research Interests: Organic Chemistry, Molecular modeling, Metabolic syndrome, Nuclear Receptor, Humans, and 15 moreMice, Animals, Natural Product, Drug Design, Molecular docking, Ganoderma Lucidum, Lipid metabolism, Model development, Chinese Herbal Medicine, National Cancer Institute, Bioorganic and medicinal Chemistry, Experimental Validation, In Silico, Bioactive Compound, and binding sites
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The κ opioid receptor (KOR) plays a significant role in many physiological functions, including pain relief, stress, depression, drug abuse, anxiety and psychotic behaviors. KORs are widely distributed in the central and peripheral... more
The κ opioid receptor (KOR) plays a significant role in many physiological functions, including pain relief, stress, depression, drug abuse, anxiety and psychotic behaviors. KORs are widely distributed in the central and peripheral nervous systems, and are specifically activated by endogenous opioids derived from prodynorphin. They are members of the G protein-coupled receptor superfamily, and the crystal structure of the human KOR was recently elucidated. KORs were initially studied for their involvement in mediation of pain as stimulation of KOR produces analgesia and minimizes abuse liability and other side effects. Nowadays, the KOR is rapidly emerging as an important target for the treatment of a variety of other human disorders. Specifically, the KOR system has become increasingly implicated as a modulator of stress-related and addictive behaviors. Several selective KOR partial agonists and antagonists have been developed as potential antidepressants, anxiolytic and anti-addiction medications. Although many KOR ligands have not demonstrated desirable pharmacological properties, some have been shown to be viable drug candidates. Herein, we describe chemical and pharmacological developments on KOR ligands, advantages and challenges, and potential therapeutic applications of ligands for KORs. In the second part, recent advances in the KOR drug design utilizing computational approaches are presented, with focus on the discovery of a new naturally derived scaffold, sewarine, as a novel class of selective KOR ligands with antagonist properties, using a pharmacophore-based virtual screening strategy.
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The κ opioid receptor (KOR) plays a significant role in many physiological functions, including pain relief, stress, depression, drug abuse, anxiety and psychotic behaviors. KORs are widely distributed in the central and peripheral... more
The κ opioid receptor (KOR) plays a significant role in many physiological functions, including pain relief, stress, depression, drug abuse, anxiety and psychotic behaviors. KORs are widely distributed in the central and peripheral nervous systems, and are specifically activated by endogenous opioids derived from prodynorphin. They are members of the G protein-coupled receptor superfamily, and the crystal structure of the human KOR was recently elucidated. KORs were initially studied for their involvement in mediation of pain as stimulation of KOR produces analgesia and minimizes abuse liability and other side effects. Nowadays, the KOR is rapidly emerging as an important target for the treatment of a variety of other human disorders. Specifically, the KOR system has become increasingly implicated as a modulator of stress-related and addictive behaviors. Several selective KOR partial agonists and antagonists have been developed as potential antidepressants, anxiolytic and anti-addiction medications. Although many KOR ligands have not demonstrated desirable pharmacological properties, some have been shown to be viable drug candidates. Herein, we describe chemical and pharmacological developments on KOR ligands, advantages and challenges, and potential therapeutic applications of ligands for KORs. In the second part, recent advances in the KOR drug design utilizing computational approaches are presented, with focus on the discovery of a new naturally derived scaffold, sewarine, as a novel class of selective KOR ligands with antagonist properties, using a pharmacophore-based virtual screening strategy.
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Microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors are considered as potential therapeutic agents for the treatment of inflammatory pain and certain types of cancer. So far, several series of acidic as well as non-acidic... more
Microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors are considered as potential therapeutic agents for the treatment of inflammatory pain and certain types of cancer. So far, several series of acidic as well as non-acidic inhibitors of mPGES-1 have been discovered. Acidic inhibitors, however, may have issues, such as loss of potency in human whole blood and in vivo, stressing the importance of the design and identification of novel, non-acidic chemical scaffolds of mPGES-1 inhibitors. Using a multistep virtual screening protocol, the Vitas-M compound library (~1.3 million entries) was filtered and 16 predicted compounds were experimentally evaluated in a biological assay in vitro. This approach yielded two molecules active in the low micromolar range (IC50 values: 4.5 and 3.8 µM, respectively).
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We report in this work the discovery of novel allosteric MEK inhibitors by pharmacophore modeling and virtual screening. Two out of 13 virtual hit compounds were identified as MEK kinase inhibitors using a MEK1 binding assay. Structural... more
We report in this work the discovery of novel allosteric MEK inhibitors by pharmacophore modeling and virtual screening. Two out of 13 virtual hit compounds were identified as MEK kinase inhibitors using a MEK1 binding assay. Structural derivations on the hit compound M100 (IC50 = 27.2 ± 4.5 μM in RAF-MEK cascading assay) by substituent transformation and bioisosterism replacement have led to the synthesis of a small library of carbazoles. The enzymatic studies revealed the preliminary structure-activity relationships and the derivative 22k (IC50 = 12.8 ± 0.5 μM) showed the most potent inhibitory effect against Raf-MEK cascading. Compound 7 was discovered as toxic as M100 to tumor cells whereas safer to HEK293 cells (IC50 > 100 μM) than M100 (IC50 = 8.9 ± 2.0 μM). It suggests that carbazole is a good scaffold for the design of novel MEK inhibitors for therapeutic uses. More importantly, the developed pharmacophore model can serve as a reliable criterion in novel MEK inhibitor discovery.
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Poster presented at EMBO Conference on Cellular Signaling & Molecular Medicine 25‐29 May 2012, Cavtat‐Dubrovnik, Croatia. This poster is published under a CC-BY license: http://dx.doi.org/10.6084/m9.figshare.1101323
Poster presented at 13th International Congress of the Society for Ethnopharmacology, Graz, Austria, September 2 – 6, 2012. This poster is published under a CC-BY license: http://dx.doi.org/10.6084/m9.figshare.1119208