General Structure-activity Relationships Research Articles

Structure-Activity Relationship and Functional Evaluation of Cannabinoid Type-1 Receptor.

The type-1 cannabinoid receptor (CB1R) is a potential therapeutic target in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Owing to their structural diversity, it is not easy to derive general structure-activity relationships (SARs) for CB1R ligands. In this study, CB1R ligands were classified into six structural families, and the corresponding SAR was determined for their affinities for CB1R. In addition, we determined their functional activities for the activation of extracellular signal-regulated kinases (ERKs). Among derivatives of indol-3-yl-methanone, the highest ligand affinity was observed when a pentyl and a naphthalenyl group were attached to the N1 position of the indole ring and the carbon site of the methanone moiety, respectively. In the case of adamantane indazole-3-carboxamide derivatives, the presence of fluorine in the pentyl group, the substituent at the N1 position of the indazole ring, strongly increased the affinity for CB1R. For (naphthalen-1-yl) methanone derivatives, the presence of 4-alkoxynaphthalene in the methanone moiety was more beneficial for the affinity to CB1R than that of a heterocyclic ring. The functional activities of the tested compounds, evaluated through ERK assay, were correlated with their affinity for CB1R, suggesting their agonistic nature. In conclusion, this study provides valuable insight for designing novel ligands for CB1R, which can be used to control psychiatric disorders and drug abuse.

General structure-activity/selectivity relationship patterns for the inhibitors of the chemokine receptors (CCR1/CCR2/CCR4/CCR5) with application for virtual screening of PubChem database

CC chemokine receptors (CCRs) form a crucial subfamily of G protein-linked receptors that play a distinct role in the onset and progression of various life-threatening diseases. The main aim of this research is to derive general structure-activity relationship (SAR) patterns to describe the selectivity and activity of CCR inhibitors. To this end, a total of 7332 molecules related to the inhibition of CCR1, CCR2, CCR4, and CCR5 were collected from the Binding Database and analyzed using machine learning techniques. A diverse set of 450 molecular descriptors was calculated for each molecule, and the molecules were classified based on their therapeutic targets and activities. The variable importance in the projection (VIP) approach was used to select discriminatory molecular features, and classification models were developed using supervised Kohonen networks (SKN) and counter-propagation artificial neural networks (CPANN). The reliability and predictability of the models were estimated using 10-fold cross-validation, an external validation set, and an applicability domain approach. We were able to identify different sets of molecular descriptors for discriminating between active and inactive molecules and model the selectivity of inhibitors towards different CCRs. The sensitivities of the predictions for the external test set for the SKN models ranged from 0.827–0.873. Finally, the developed classification models were used to screen approximately 2 million random molecules from the PubChem database, with average values for areas under the receiver operating characteristic curves ranging from 0.78–0.96 for SKN models and 0.75–0.89 for CPANN models. Communicated by Ramaswamy H. Sarma

Nanozymes Inspired by Natural Enzymes

ConspectusNanozymes, nanomaterials with enzyme-like activities with high structural stability, adjustable catalytic activity, functional diversity, recyclability, and feasibility in large-scale preparation, have become a hot spot in the field of artificial enzymes in recent years and are expected to become potential surrogates and competitors for natural enzymes in practical applications. With the development of in-depth research and a wide range of application requirements, creating nanozymes with catalytic performance comparable to or even surpassing that of natural enzymes has been the key research topic in this field. Most of the nanozymes reported in the past were obtained based on random synthesis and screening, for which the catalytic efficiency is far inferior to that of natural enzymes. Natural enzymes that have evolved over hundreds of millions of years have developed a lot of high-efficiency catalysis know-how hidden in their structural features. To create highly active nanozymes, we assumed that there is a general structure–activity relationship between nanozymes and natural enzymes and proposed the nanozyme optimization strategy by grafting the catalytic principles of natural enzymes into the rational design of nanozymes. On the basis of this bioinspired strategy, a series of nanozymes that exhibit similar catalytic activities that are closer to or even beyond those of natural enzymes have been successfully synthesized. By now, rationally designed high-activity bioinspired nanozymes have become a hot topic in the current research on nanozymes.In this Account, we focus on recent representative research progress in the systemic design and construction of bioinspired nanozymes and are devoted to introducing strategic concepts in the bioinspired optimization of nanozymes. We show that the de novo design of nanozymes by simulating the amino acid microenvironment and using metal-free architecture and the coordination structure of metal active sites in natural enzymes is an effective strategy for significantly improving the catalytic performance of nanozymes. A future perspective of the challenges and countermeasures of bioinspired nanozymes is proposed on the basis of these achievements. We hope that the biologically inspired perception will arouse widespread interest in fundamental research and practical applications as well as provide inspiration for the rational design of nanozymes.

Rational Design of Novel Phosphoinositide 3-Kinase Gamma (PI3Kγ) Selective Inhibitors: A Computational Investigation Integrating 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation.

Phosphoinositide 3-kinase gamma (PI3Kγ) draws an increasing attention due to its link with deadly cancer, chronic inflammation and allergy. But the development of PI3Kγ selective inhibitors is still a challenging endeavor because of the high sequence homology with the other PI3K isoforms. In order to acquire valuable information about the interaction mechanism between potent inhibitors and PI3Kγ, a series of PI3Kγ isoform-selective inhibitors were analyzed by a systematic computational method, combining 3D-QSAR, molecular docking, molecular dynamic (MD) simulations, free energy calculations and decomposition. The general structure-activity relationships were revealed and some key residues relating to selectivity and high activity were highlighted. It provides precious guidance for rational virtual screening, modification and design of selective PI3Kγ inhibitors. Finally, ten novel inhibitors were optimized and P10 showed satisfactory predicted bioactivity, demonstrating the feasibility to develop potent PI3Kγ inhibitors through this computational modeling and optimization.

Recent Advances in the Exploration of Therapeutic Analogues of Gramicidin S, an Old but Still Potent Antimicrobial Peptide.

Gramicidin S (GS), one of the oldest commercially used peptide antibiotics, is known for its robust antibacterial activity against both Gram-positive and Gram-negative bacterial strains. Although it was discovered well over 70 years ago, its clinical potential was limited to topical applications because of its high hemolytic activity. To overcome this side effect, significant efforts have been invested in the chase for GS analogues with high therapeutic index (e.g., high antimicrobial activity and low hemolytic activity) in the past decades. In this Perspective, the structural properties and biological profiles (including the recently discovered activities) of representative GS analogues designed by different approaches are described and analyzed. We also present how the general structure-activity relationships were established and how they could help in the design of more efficient GS analogues.

Piperlongumine (piplartine) as a lead compound for anticancer agents – Synthesis and properties of analogues: A mini-review

Piperlongumine, also known as piplartine, is an amide alkaloid of Piper longum L. (long piper), a medical plant known from Ayurvedic medicine. Although was discovered well over fifty years ago, its pharmacological properties have been uncovered in the past decade. In particular, piperlongumine has been most extensively studied as a potential anticancer agent. Piperlongumine has exhibited cytotoxicity against a broad spectrum of human cancer cell lines, as well as demonstrated antitumor activity in rodents. Piperlongumine has also been found to be a proapoptotic, anti-invasive, antiangiogenic agent and synergize with modern chemotherapeutic agents. Because of its clinical potential, several studies were undertaken to obtain piperlongumine analogues, which have exhibited more potent activity or more appropriate drug-like parameters. In this review, the synthesis of piperlongumine analogues and piperlongumine-based hybrid compounds, as well as their anticancer properties and the molecular basis for their activity are explored. General structure-activity relationship conclusions are drawn and directions for the future research are indicated.

General Synthetic Method for Si-Fluoresceins and Si-Rhodamines.

The century-old fluoresceins and rhodamines persist as flexible scaffolds for fluorescent and fluorogenic compounds. Extensive exploration of these xanthene dyes has yielded general structure–activity relationships where the development of new probes is limited only by imagination and organic chemistry. In particular, replacement of the xanthene oxygen with silicon has resulted in new red-shifted Si-fluoresceins and Si-rhodamines, whose high brightness and photostability enable advanced imaging experiments. Nevertheless, efforts to tune the chemical and spectral properties of these dyes have been hindered by difficult synthetic routes. Here, we report a general strategy for the efficient preparation of Si-fluoresceins and Si-rhodamines from readily synthesized bis(2-bromophenyl)silane intermediates. These dibromides undergo metal/bromide exchange to give bis-aryllithium or bis(aryl Grignard) intermediates, which can then add to anhydride or ester electrophiles to afford a variety of Si-xanthenes. This strategy enabled efficient (3–5 step) syntheses of known and novel Si-fluoresceins, Si-rhodamines, and related dye structures. In particular, we discovered that previously inaccessible tetrafluorination of the bottom aryl ring of the Si-rhodamines resulted in dyes with improved visible absorbance in solution, and a convenient derivatization through fluoride-thiol substitution. This modular, divergent synthetic method will expand the palette of accessible xanthenoid dyes across the visible spectrum, thereby pushing further the frontiers of biological imaging.

ChemInform Abstract: Discovery of HCV NS5B Thumb Site I Inhibitors: Core‐Refining from Benzimidazole to Indole Scaffold

AbstractReview: 45 refs.

Discovery of HCV NS5B thumb site I inhibitors: Core-refining from benzimidazole to indole scaffold

Hepatitis C virus (HCV) NS5B RNA-depended-RNA-polymerase (RdRp) is an essential enzyme in HCV viral replication and has no functional equivalent in mammalian cells. Several classes of nucleoside and non-nucleoside inhibitors, targeting the different allosteric sites, have demonstrated efficacy in clinical trials. Compared to other allosteric sites, thumb site I is a more compelling allosteric target with a significant number of inhibitors in clinical trials. Among them, indole analogues are the most important series of NS5B thumb site I inhibitors with considerable antiviral activity. This review focuses on the discovery and development of indole inhibitors targeting on NS5B thumb site I. Five fundamental principles, the general structure–activity relationships (SARs) model of indole scaffold, were summarized, which could pave the way for further structural optimization of indole-based anti-HCV agents.

Development of Polyphenols as HIV-1 Integrase Inhibitors: a Summary and Perspective

Raltegravir, the only drug targeting the integration step in HIV-1 life cycle, makes β-ketoenol integrase (IN) strand transfer inhibitor (STI) gain a definitive place in the treatment of HIV-1 infection. However, the emergence of viral strains resistant to β-ketoenol STI demands a continued effort toward the discovery of novel IN inhibitors interfering with HIV-1 IN in a mechanistically different manner. Polyphenols, among the most developed IN inhibitors, exhibit a different mechanism of action compared with β-ketoenol STI. Some of them exhibit strong IN inhibitory activity and anti-viral activity at nanomolar level and 1,5-DCQA has been in phase II clinical trial in China. It is undoubted that this kind of compounds are attractive candidates for future inhibitor design, as they should be effective against STI resistant viral strains and display synergistic effect when combined with the current existing STI. However, almost all reviews about IN inhibitors have been focused on β-ketoenol STI, while the thorough evolution and general structure-activity relationship (SAR) summaries of polyphenols as IN inhibitors had never been specially discussed. In this review, we provide a comprehensive report of the nearly twenty years development of polyphenols as IN inhibitors: summarizing general SAR and suggesting the orientation for further research. Compilation of such data will prove beneficial in developing a novel generation of IN inhibitors.

Classification of anti-HIV compounds using counterpropagation artificial neural networks and decision trees

The main aim of the present work was to collect and categorize anti-HIV molecules in order to identify general structure–activity relationships. In this respect, a total of 5580 drugs and drug-like molecules was collected from 256 different articles published between 1992 and 2010. An algorithm called genetic algorithm–pattern search counterpropagation artificial neural networks (GPS-CPANN) was proposed for the classification of compounds. In addition, the CART (classification and regression trees) method was used for construction of decision trees and finding the best molecular descriptors. The results revealed that the developed CPANN models and decision tree can correctly classify the molecules according to their inhibition mechanisms and activities. Some general parameters such as molecular weight, average molecular weight, number of hydrogen atoms and number of hydroxyl groups were found to be important for describing the inhibition behaviour of anti-HIV agents. The developed classifier models in this work can be used to screen large libraries of compounds to identify those likely to display activity as anti-HIV agents.

Mitragyna speciosa, A Psychoactive Tree from Southeast Asia with Opioid Activity

Mitragyna speciosa Korth. (Rubiaceae) is a tree that is commonly found in Southeast Asia. Leaves from this tree have been traditionally been used for both their stimulant properties as well as an opium substitute. The tree/leaves are currently illegal in four countries, but is currently legal and widely available in the United States. To date over 40 compounds have been isolated from the leaves. The major alkaloid found within the crude extract, mitragynine, has been the subject of many pharmacological studies. In addition to the pharmacological studies, two total syntheses of mitragynine have been published as well as general structure-activity relationships (SARs) with respect to opioid activity.

Nuclear receptor engineering based on novel structure activity relationships revealed by farnesyl pyrophosphate

Nuclear receptors (NRs) comprise the second largest protein family targeted by currently available drugs, acting via specific ligand interactions within the ligand binding domain (LBD). Recently, farnesyl pyrophosphate (FPP) was shown to be a unique promiscuous NR ligand, activating a subset of NR family members and inhibiting wound healing in skin. The current study aimed at visualizing the unique basis of FPP interaction with multiple receptors in order to identify general structure-activity relationships that operate across the NR family. Docking of FPP to the 3D structures of the LBDs of a diverse set of NRs consistently revealed an electrostatic FPP pyrophosphate contact with an NR arginine conserved in the NR family, a hydrophobic farnesyl contact with NR helix-12 and a ligand binding pocket volume between 300 and 430 Å(3) as the minimal requirements for FPP activation of any NR. Lack of any of these structural features appears to render a given NR resistant to FPP activation. We used these structure-activity relationships to rationally design and successfully engineer several mutant human estrogen receptors that retain responsiveness to estradiol but no longer respond to FPP.

Crystal Structure of 3-(4-Methoxy-benzylidene)-isothiochroman-4-one

Abstract The title compound, 3-(4-methoxy-benzyli-dene)-isothiochroman-4-one (C 17 H 14 O 2 S) was preparedfrom the reaction of isothiochroman-4-one with benzalde-hyde in the presence of small amount of HCl. The structureof the synthesised compound was determined by IR, 1 HNMR and X-ray crystallography. The structure was solvedin monoclinic, space group P2 1 /n with a = 3.9773 (7) A˚ ,b = 10.918 (2) A˚ , c = 30.609 (6) A˚ , b = 90.615 (3) ,V = 1329.1 (4) A˚ 3 ,Z= 4 and with R int = 0.047. Thebicyclic ring of isothiochroman-4-one moiety does notadopt a planar geometry. The molecular conformation isstable via C10–H O1 and C16–H S1 intramolecularhydrogen-bonding interactions. These contacts involvemolecules in an extended two-dimensional sheet to the bcplane.Keywords Crystal structure 3-(4-Methoxy-benzylidene)-isothiochroman-4-one Benzaldehyde Isothiochroman-4-oneIntroductionSpiro-heterocyclic compounds containing one or two func-tionalised arms at various positions have emerged aspotentially interesting drugs owing to their patented selec-tive antitumoral behaviour against breast-cancer (MCF7-strains) [1], antitubercular agents [2] or anti-HIV agents [3].These studies showed that spiro-heterocyclic compoundsbearing an oxygen or sulfur heteroatom in the 3-position/C=O are highly active not only as anti-tubercular oranti-HIV agents but as potential combined antitubercular/anti-HIV agents [4]. From the general structure–activityrelationship, it appears that functionalized side chain(s)characterised by pendant sites such as (O=C–Y–Z), whereY–Z is N=N or O–N, are crucial for bioactivity. Theincorporated heteroatom centres S or O on 3-position seemto have critical interactions with the bacterial cell receptorsor may be as centre donors in metal complexation. Theisothiochroman-4-one, was prepared since a long time [5]by cyclising the chloride 4-phenyl-3-thiabutanoi¨c acid innitrobenzene in presence of tri-chloride aluminium. Thechloride 4-phenyl-3-thiabutanoi¨c acid has been cyclisedby addition of trichloride aluminium in a mixture of(chloroforme/disulfure-carbone). A group of researcher [6]has improved its yield by cyclising the 4-phenyl-3-thiabut-anoi¨cacid(3)byadditionofphosphoricanhydride[P

Radioligand Development for PET Imaging of β-Amyloid (Aβ)-Current Status

Two of the main pathological hallmarks of Alzheimer's disease (AD) are neuritic plaques and neurofibrillary tangles. Significant evidence supports a critical and probable causative role of beta amyloid (Abeta) plaque formation. Since neuroprotective treatments are typically most effective at early stages of injury, the detection and measurement of Abeta load in living brain should be performed at early and perhaps even presymptomatic stages of AD. Two primary targets of molecular imaging research with positron emission tomography (PET) are to develop surrogate markers (radioligands) for assessing disease progression and for monitoring the efficacy of developmental therapeutics. Here, we review the current status of radioligand development for PET imaging of Abeta aggregates. General structure-activity relationships have emerged, including the identification of at least three different ligand binding sites in various Abeta aggregates and recognition of the general structural requirements for ligand binding at each site. Also a few radioligands applicable to imaging Abeta plaques in living human brain with positron emission tomography (PET) have emerged, including [(11)C]PIB, [(11)C]SB-13 and [(18)F]FDDNP.

Kinetic parameters for gas-phase reactions: Experimental and theoretical challenges

This article aims to illustrate the added value provided to experimental kinetics investigations by complementary theoretical kinetics studies, using as examples (i) reactions of two major hydrocarbon flame radicals, HCCO and C(2)H, and (ii) reactions of several oxygenated organic compounds with hydroxyl radicals of interest to atmospheric chemistry. The first part, on HCCO and C(2)H kinetics, does not attempt to give an extensive literature review, but rather addresses some major experimental techniques, mainly specific ones, that have allowed a great part of the available reactivity databases on these two species to be established. For several key reactions, it is shown how potential energy surfaces and statistical rate predictions based thereon have provided insight into the molecular mechanisms and have allowed estimates of product distributions as well as reliable extrapolations of experimental rate coefficients and branching ratios to higher temperatures. The second part addresses current issues in atmospheric chemistry relating mainly to hydroxyl radical reactions with oxygenated organics, and focuses on the experimental characterization of the often unusual temperature dependence of their rate coefficients and on the theoretical rationalization thereof, through the formation of hydrogen-bonded pre-reactive complexes and resulting tunnelling-enhanced H-abstraction. Finally, the development of general structure-activity relationships for OH reactions with organics, H-abstractions as well as OH-additions for unsaturated compounds, is briefly discussed.

Influence of Functional Group Substitutions on the Carcinogenicity of Anthraquinone in Rats and Mice: Analysis of Long-Term Bioassays by the National Cancer Institute and the National Toxicology Program

The carcinogenic activities of anthraquinone and six derivatives were compared and contrasted. Studies included representatives of amino, alkyl, nitro, hydroxy, or halogen-containing anthraquinones, with the purpose of uncovering general structure–activity relationships. Anthraquinone, 2-aminoanthraquinone, 1-amino-2-methylanthraquinone, 2-methyl-1-nitroanthraquinone, 1‐amino-2,4-dibromoanthraquinone, 1,4,5,8-tetraaminoanthraquinone, and 1,3,8-trihydroxy-6-methylanthraquinone (of varying purities) were administered via feed to Fischer 344/N rats and B6C3F1 mice. In rats, anthraquinone induced tumors in the liver, kidney, and urinary bladder. A 2-amino substitution narrowed the carcinogenicity to the liver, while multiple amino substitutions led to a carcinogenic response in the urinary bladder alone. A methyl substitution ortho to a 1-amino group preserved the hepatic and renal neoplasms seen with the parent anthraquinone, but did not induce urinary bladder tumors; amino or bromo substitutions para to a 1-amino group were related to urinary bladder neoplasms. The intestine may have been a target organ for bromine-substituted anthraquinones. The presence of a nitro group altered the targets of carcinogenicity, and skin tumors may have been associated with this particular functional group in both rats and mice. Overall for mice, the findings were somewhat different and limited by the small number of common target organs. The parent anthraquinone was clearly carcinogenic only to the liver. There were no other effects of single amino substitutions, in the presence or absence of an additional methyl group, on the carcinogenicity or the site of carcinogenesis of anthraquinone in mice. Multiple amino substitutions diminished, while bromine substitutions enhanced the carcinogenicity induced by anthraquinone and extended the target organs to include forestomach and lung. The authors are grateful to Drs. Tom Burka and James Huff for reviewing the manuscript of this article. The contribution of Dr. Doug Bristol is greatly appreciated. The authors also acknowledge the contribution of all study scientists and other personnel involved in the anthraquinone NCI and NTP studies.

Nonsteroidal aromatase inhibitors: recent advances.

Aromatase is the cytochrome P450 enzyme responsible for the last step of estrogen biosynthesis, and aromatase inhibitors constitute an important class of drugs in clinical use for the treatment of breast cancer. Nonsteroidal aromatase inhibitors (NSAIs) are competitive inhibitors of aromatase, which bind to the enzyme active site by coordinating the iron atom present in the heme group of the P450 protein. Presently, third generation NSAIs are in use, and research efforts are being carried out both to identify new molecules of therapeutic interest and to clarify the mechanism of action. In this article, we present a survey of the compounds that have been recently reported as NSAIs, to provide a broad view on the general structure-activity relationships of the class. Moreover, starting from the current knowledge of the mechanistic aspects of aromatase action and from recent theoretical work on the molecular modeling of both enzyme and inhibitors, we try to indicate a way to integrate these different studies in view of a more general understanding of the aromeatase-inhibitor system. Finally, some aspects regarding the possible future development of the field are considered briefly.

A Noncongeneric Model for Predicting Toxicity of Organic Molecules to Vibrio Fischeri

A general Quantitative Structure-Activity Relationship (QSAR) model on Vibrio fischeri (Microtox™ test) was derived using the autocorrelation method for describing the molecules and a neural network as statistical tool. From a training set of 1068 organic chemicals described by means of four different autocorrelation vectors, it was possible to obtain valuable models but presenting some large outliers. Addition of the time of exposure as variable allowed us to derive a more powerful model from 2795 toxicity results. The predictive power of this 36/26/1 neural network model was tested on an external testing set of 385 toxicity data and compared with the performances of linear models designed for polar narcotic amines and for weak acid respiratory uncouplers.

6‐Methylflavone, a benzodiazepine receptor ligand with antagonistic properties on rat brain and human recombinant GABAA receptors in vitro

Seventeen flavonoids were found to have inhibitory activity on the central nervous system GABAA/benzodiazepine (BZD) receptors with IC50 values ranging from 0.12 to 8 μM. 6-Methylflavone, the most potent, was pharmacologically characterized by radioligand binding assays on rat brain membranes in vitro and human recombinant GABAA/BZD receptors expressed in Sf-9 insect cells, as well as electrophysiologically by the whole-cell patch clamp technique. Scatchard plot analysis showed that 6-methylflavone was a competitive inhibitor of [3H]-Ro 15-1788, binding to rat brain cortical membranes. The GABA ratio of 1.06 for [3H]-diazepam binding to cortex and 1.23 for cerebellum indicated an antagonistic or a weak partial agonistic profile of 6-methylflavone on the rat BZD1 receptors, while the GABA ratio of 0.76 on hippocampus indicated an antagonistic or partial-inverse agonistic profile on the BZD2 receptors. In Sf-9 insects cells, the GABA ratios showed a weak partial agonistic profile on the α1β2γ2S (GABA ratio 1.29) subtype combination, an antagonistic profile on the α2β2γ2S (1.13) and α3β2γ2S (1.03), and a partial inverse agonistic profile on the α5β2γ2S (0.79) subtype combination. The modulation of GABA-induced chloride currents by 6-methylflavone suggests that the compound is an antagonist at human GABAA receptor subtypes. Based on our data of GABAA/BZD receptor active as well as inactive flavonoids, some general structure–activity relationships are discussed. Drug Dev. Res. 41:99–106, 1997. © 1997 Wiley-Liss, Inc.