The Journal of Computer-Aided Molecular Design: a bibliometric note

Summarizes the articles in, and the citations to, volumes 2-24 of the Journal of Computer-Aided Molecular Design. The citations to the journal come from almost 2000 different sources that span a very wide range of academic subjects, with the most heavily cited articles being descriptions of software systems and of computational methods

Ligand-based pharmacophore modeling using novel 3D pharmacophore signatures

© 2018 by the authors. Pharmacophore modeling is a widely used strategy for finding new hit molecules. Since not all protein targets have available 3D structures, ligand-based approaches are still useful. Currently, there are just a few free ligand-based pharmacophore modeling tools, and these have a lot of restrictions, e.g., using a template molecule for alignment. We developed a new approach to 3D pharmacophore representation and matching which does not require pharmacophore alignment. This representation can be used to quickly find identical pharmacophores in a given set. Based on this representation, a 3D pharmacophore ligand-based modeling approach to search for pharmacophores which preferably match active compounds and do not match inactive ones was developed. The approach searches for 3D pharmacophore models starting from 2D structures of available active and inactive compounds. The implemented approach was successfully applied for several retrospective studies. The results were compared to a 2D similarity search, demonstrating some of the advantages of the developed 3D pharmacophore models. Also, the generated 3D pharmacophore models were able to match the 3D poses of known ligands from their protein-ligand complexes, confirming the validity of the models. The developed approach is available as an open-source software tool: http://www.qsar4u.com/pages/pmapper.php and https://github.com/meddwl/psearch

Investigation Of The Allosteric Modulators Desformylflustrabromine And 4-(2-Hydroxyethyl)-1-Piperazineethanesulfonic Acid (Hepes) Interactions On Nicotinic Acetylcholine Receptors

Thesis (Ph.D.) University of Alaska Fairbanks, 2011Neuronal nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop super family of ligand gated ion channels. Dysregulation of nAChRs can lead to pathologies such as Alzheimer's disease, Parkinson's disease, Autism and nicotine addiction. Possible new therapeutic avenues are positive allosteric modulators (PAMs). The natural product desformylflustrabromine (dFBr), a tryptophan metabolite of the marine bryozoan Flustra foliacea, was found to be PAM of alpha4beta2 nAChR. Evaluation of our synthetic water soluble dFBr salt by two-electrode voltage clamp of Xenopus laevis oocytes expressing human nAChR confirmed that synthetic dFBr displayed similar properties as the natural product. Low concentrations of the synthetic dFBr enhanced ACh's efficacy on alpha4beta2 receptors. At higher dFBr concentrations, dFBr inhibited ACh potentiated responses. On alpha7 receptors, dFBr inhibited ACh induced currents. Further pharmacological characterization of dFBr revealed that dFBr was able to enhance partial agonist potencies and efficacies. Evaluation of dFBr on antagonists showed no effect on antagonist inhibition. The mechanisms of biphasic modulation (potentiation and inhibition) of dFBr on alpha4beta2 nAChR were also investigated. Enhanced efficacy of ACh induced currents by dFBr appeared to be accomplished by dFBr stabilization of the open receptor conformation by destabilization of the desensitized state. The inhibition of ACh potentiated currents by dFBr appeared to involve open-channel block. To better understand dFBr mechanisms, its putative binding site was examined. Alanine mutations were made in non-orthosteric clefts on the beta2+ and alpha4- faces. Results revealed residues located on these faces are involved in ACh induced conformational change of the receptor. In addition our data supports our hypothesis that allosteric modulation by dFBr interacts with residues located on the beta2+ and alpha4- faces. The new novel actions of (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES) as a alpha4beta2 stoichiometric PAM was discovered and characterized. We showed that HEPES, a common buffering agent, potentiated the high ACh sensitivity alpha4beta2 receptor while only inhibiting the low ACh sensitivity alpha4beta2 receptor. Mutagenesis results suggested that residue beta2D217 is a critical residue in the HEPES binding site. Results from these studies will aid in the development of therapeutic ligands that will assist in the treatment of diseases where nAChRs are dysregulated

Graph theoretic methods for the analysis of structural relationships in biological macromolecules

Subgraph isomorphism and maximum common subgraph isomorphism algorithms from graph theory provide an effective and an efficient way of identifying structural relationships between biological macromolecules. They thus provide a natural complement to the pattern matching algorithms that are used in bioinformatics to identify sequence relationships. Examples are provided of the use of graph theory to analyze proteins for which three-dimensional crystallographic or NMR structures are available, focusing on the use of the Bron-Kerbosch clique detection algorithm to identify common folding motifs and of the Ullmann subgraph isomorphism algorithm to identify patterns of amino acid residues. Our methods are also applicable to other types of biological macromolecule, such as carbohydrate and nucleic acid structures

Investigation on Quantitative Structure Activity Relationships and Pharmacophore Modeling of a Series of mGluR2 Antagonists

MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson’s disease and schizophrenia. Herein, we report the three-dimensional quantitative structure–activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[ b][1,4]diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [3H]-LY354740; activity II: mGluR2 (1S,3R)-ACPD inhibition of forskolin stimulated cAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q2 of 0.513, R2 ncv of 0.868, R2 pred = 0.876, while the CoMSIA model yielded a Q2 of 0.450, R2 ncv = 0.899, R2 pred = 0.735. For activity II study, CoMFA model yielded statistics of Q2 = 0.5, R2 ncv = 0.715, R2 pred = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R7, R3 and position A benefit activity I of the antagonists, but decrease it when projected in R8 and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity. This work is the first report on 3D-QSAR modeling of these mGluR2 antagonists. All the conclusions may lead to a better understanding of the mechanism of antagonism and be helpful in the design of new potent mGluR2 antagonists

Drug design for ever, from hype to hope

In its first 25 years JCAMD has been disseminating a large number of techniques aimed at finding better medicines faster. These include genetic algorithms, COMFA, QSAR, structure based techniques, homology modelling, high throughput screening, combichem, and dozens more that were a hype in their time and that now are just a useful addition to the drug-designers toolbox. Despite massive efforts throughout academic and industrial drug design research departments, the number of FDA-approved new molecular entities per year stagnates, and the pharmaceutical industry is reorganising accordingly. The recent spate of industrial consolidations and the concomitant move towards outsourcing of research activities requires better integration of all activities along the chain from bench to bedside. The next 25 years will undoubtedly show a series of translational science activities that are aimed at a better communication between all parties involved, from quantum chemistry to bedside and from academia to industry. This will above all include understanding the underlying biological problem and optimal use of all available data

Biochemistry of opioid (morphine) receptors : binding, structure and molecular modelling

Morphine is the most widely used compound among narcotic analgesics and remains the gold standard when the effects of other analgetic drugs are compared. The most characteristic effect of morphine is the modulation of pain perception resulting in an increase in the threshold of noxious stimuli. Antinociception induced by morphine is mediated via opioid receptors, namely the μ-type opioid receptor. Apart from the μ-opioid receptor, two other classical opioid receptors κ- and δ- and one non-classical opioid receptor, the nociceptin receptor was discovered and cloned so far. At the same time endogenous opioids were also discovered, such as enkephalins, endorphins, and dynorphins. The opioid receptors together with the endogenous opioids form the so called endogenous opioid system, which is highly distributed throughout the body and apart from analgesia it has several other important physiological functions. In this article we will review the historical milestones of opioid research − in detail with morphine. The review will also cover the upmost knowledge in the molecular structure and physiological effects of opioid receptors and endogenous opioids and we will discuss opioid receptor modelling − a rapidly evolving field in opioid receptor research

Part I. The First Enantiospecific, Stereospecific Total Synthesis of the Indole Alkaloid Ervincidine. Part II. The Synthesis of Alpha 5 Subtype Selective Ligands for Gaba(a) /Benzodiazepine Receptors

Part I. The first enantiospecific, stereospecific total synthesis of ervincidine 89 has been accomplished from commercially available D-(+)-tryptophan 37 which has served both as the chiral auxiliary and the starting material. Moreover, this is the first synthesis which unequivocally sets the stereochemistry of the hydroxyl group at C-6 in sterospecific fashion, as well as the C-16 hydroxy methyl group. The stereospecific conversion of D-(+)-tryptophan 37 into the key template (−)-Na-H, Nb-benzyl tetracyclic ketone 49 via the asymmetric Pictet-Spengler reaction (600 gram scale) and Dieckmann cyclization on multi-hundred gram scale was reduced to only two reaction vessels. The optically active tetracyclic ketone 49 was converted into the core pentacyclic framework 56 using the intramolecular palladium-mediated enolate cross coupling reaction which was developed here in Milwaukee to afford the core pentacylic framework 56. This robust reaction could be scaled up to multigram scale in this series. Important to success here were the sequence of chemical reactions which included a Wittig reaction, a regioselective hydroboration and protection/deprotection steps in order to provide regiospecific oxidation at C-6. The IBX mediated oxidation and the Luche reduction using CeCl3. 7H20 in the presence of NaBH4 afforded the first enantiospecific, stereospecific total synthesis of ervincidine 89. The indole alkaloid ervincidine 89 could be prepared from D-(+)-tryptophan 37 in 13 reaction vessels in 19.2% overall yield. Another important experiment was the epimerization of the C-6 alcohol with 0.2N HCl which indicated that care must be employed in isolation of these alkaloids which contain a benzylic hydroxyl group. This research process developed here also provides a general entry to the C-6 hydroxy substituted indole alkaloids of either alpha or beta stereochemistry. Two other diasteromers were made to rule them out as potential structures. This research corrects the errors in Glasby\u27s book and Lousnamma\u27s review and clarifies the work of Yunusov et al. as well as providing the correct absolute configuration of the C-6 hydroxyl function in ervincidine 89. Part.II..GABAA/BzR chloride ion channels comprise the major inhibitory neurotransmitter system in the CNS. This central role carries with it a direct influence on many diseases of the CNS. Inverse agonists acting at α5 subunits containing GABAA receptors are thought to act as cognitive enhancers while eliminating unwanted side effects associated with non-selective compounds. From the recent work of Rowlett, Cook et.al. it was demonstrated that novel alpha5 selective inverse agonist PWZ-029 was evaluated as a cognitive enhancer in rhesus monkeys in the CANTAB paradigm. This ligand had the ability to reverse cholinergic deficits in performance induced by the antimuscarinic scopolamine under mixed trial conditions. In the ORD task, PWZ-029 showed only a modest trend for enhancement of performance, but when task difficulty was increased by testing with difficult trials only, PWZ-029 robustly increased performance. This enhancement was reversed by administration of the alpha 5 GABA (A) subtype selective antagonist XLi-093 and this antagonism in turn was reversed by increasing the dose of PWZ-029. In addition, PWZ-029 enhanced performance in the DNMS task using the 10 minute delay with distracters. This ligand also exhibited anxiolytic activity in some primates and was an orally active anticonvulsant in rats. These findings are consistent with a key role for alpha5 GABAA receptors in the treatment of age-associated memory impairment and Alzheimer\u27s disease

Synthesis of Subtype Selective Bz/GABAA Receptor Ligands for the Treatment of Anxiety, Epilepsy and Neuropathic Pain, as Well as Schizophrenia and Asthma

The α2/α3 subtype selective Bz/GABAA receptor positive allosteric modulator HZ-166 (3) has been shown to be a nonsedating anxiolytic with anticonvulsant and antihyperalgesic activity. However, instability in vitro and in vivo has hindered its advancement into clinical trials. A series of ligands based off HZ-166 (3) were synthesized. Many of these ligands were designed to increase metabolic stability, while others were synthesized to study the effects that electronics and sterics have on the efficacy exerted when bound to the GABAA receptor. The α3 subtype selective methyl ester MP-III-024 (19) was shown to have increased resistance to metabolism in in vitro liver microsomal studies and exhibited significant anxiolytic and antihyperalgesic effects in mice without showing signs of sedation. However, pharmacokinetic studies indicated that esters as a functional group may not be suitable for extensive preclinical studies. A series of heterocyclic bioisosteres were synthesized to specifically overcome short half-lives in vivo. The oxadiazole MP-III-080 (34) and oxazole KRM-II-81 (36) underwent pharmacokinetic studies and were both found to exist in plasma and brain samples in high levels. These results indicated that these and related heterocycles would be stable in vivo to undergo extensive preclinical trials. A dozen ligands were assessed in vivo in an anxiolytic marble burying assay and a rotarod assay designed to measure ataxic effects. The results from these studies and other in vitro protocols led to additional studies using KRM-II-81 (36). This oxazole 36 was found to exhibit significant anxiolytic and anticonvulsant properties, including reducing network firing rate frequency in human brain tissue from a patient suffering from resistance epilepsy. In addition, KRM-II-81 (36) was found to be more efficacious than gabapentin to reverse the effects of hyperalgesia in a neuropathic pain model at a lower dose using rats, as well as exhibiting antidepressant-like effects. The α5 GABAA receptor subtype has been linked to the cognitive disorders in such diseases as schizophrenia, bipolar I disorder and major depressive disorder. The enantiomers SH-053-2\u27F-S-CH3 (51) and SH-053-2\u27F-R-CH3 (52) have been shown to be α2/α3/α5- and α5- subtype selective agonists, respectively. Both ligands (S)-51 and (R)-52 have been shown to reduce some positive symptoms of schizophrenia; the S-enantiomer 51 was active in the poly(I:C) model of schizophrenia while the R-enantiomer 52 was active in the MAM-model of schizophrenia. Due to the high rate of comorbidity of schizophrenia with anxiety, epilepsy and depression, the S-enatiomer (51) is shown here to be useful in these instances exhibiting anxiolytic and anticonvulsant properties. In addition, work on analogs of 52 produced MP-III-004 (63), an α5 subtype selective ligand with reduced efficacy at the α1, α2 and α3 subtypes as compared to 52, as well as the very potent α5 positive allosteric modulator MP-III-022 (65). This methyl amide 65 was shown to activate α5 subtypes in vivo in rats at low concentrations, providing a valuable tool to study the α5 GABAA receptor subtype. Recent work has shown SH-053-2\u27F-R-CH3 (52) and MP-III-022 (65) exert antidepressant-like effects in mice, indicating a new use for α5 subtype selective ligands. Moreover, work by Emala et al. has discovered a use for α5 subtype selective ligands outside of the central nervous system. A number of the ligands, especially the α5 selective acid 73, presented herein have been shown to relax precontracted human and guinea pig airway smooth muscle and may provide a novel treatment for those who suffer from asthma