Current Structure-activity Relationship Research Articles

A Systematic Hierarchical Virtual Screening Model for RhlR Inhibitors Based on PCA, Pharmacophore, Docking, and Molecular Dynamics.

RhlR plays a key role in the quorum sensing of Pseudomonas aeruginosa. The current structure-activity relationship (SAR) studies of RhlR inhibitors mainly focus on elucidating the functional groups. Based on a systematic review of previous research on RhlR inhibitors, this study aims to establish a systematic, hierarchical screening model for RhlR inhibitors. We initially established a database and utilized principal component analysis (PCA) to categorize the inhibitors into two classes. Based on the training set, pharmacophore models were established to elucidate the structural characteristics of ligands. Subsequently, molecular docking, molecular dynamics simulations, and the calculation of binding free energy and strain energy were performed to validate the crucial interactions between ligands and receptors. Then, the screening criteria for RhlR inhibitors were established hierarchically based on ligand structure characteristics, ligand-receptor interaction, and receptor affinity. Test sets were finally employed to validate the hierarchical virtual screening model by comparing it with the current SAR studies of RhlR inhibitors. The hierarchical screening model was confirmed to possess higher accuracy and a true positive rate, which holds promise for subsequent screening and the discovery of active RhlR inhibitors.

Optimization of pyridylpiperazine-based inhibitors of the Escherichia coli AcrAB-TolC efflux pump

Multidrug–resistant Escherichia coli is a continuously growing worldwide public health problem, in which the well-known AcrAB-TolC tripartite RND efflux pump is a critical driver. We have previously described pyridylpiperazines as a novel class of allosteric inhibitors of E. coli AcrB which bind to a unique site in the protein transmembrane domain, allowing for the potentiation of antibiotic activity. Here, we show a rational optimization of pyridylpiperazines by modifying three specific derivatization points of the pyridine core to improve the potency and the pharmacokinetic properties of this chemical series. In particular, this work found that the introduction of a primary amine to the pyridine through ester (29, BDM91270) or oxadiazole (44, BDM91514) based linkers allowed for analogues with improved antibiotic boosting potency through AcrB inhibition. In vitro studies, using genetically engineered mutants, showed that this improvement in potency is mediated through novel interactions with distal acidic residues of the AcrB binding pocket. Of the two leads, compound 44 was found to have favorable physico-chemical properties and suitable plasma and microsomal stability. Together, this work expands the current structure-activity relationship data on pyridylpiperazine efflux pump inhibitors, and provides a promising step towards future in vivo proof of concept of pyridylpiperazines as antibiotic potentiators.

Discovery of pyrazole-1-carboxamide derivatives as novel Gi-biased μ-opioid receptor agonists.

μ-Opioid receptor (MOR) Gi-biased agonists with no recruitment of β-arrestin were introduced as a new analgesic strategy to overcome the conventional undesirable side effects of opioid receptor-targeted drugs, such as tolerance, addiction, respiratory depression, and constipation. For the development of novel Gi-biased MOR agonists, the design, synthesis, and structure-activity relationship(SAR) analysis of the aminopyrazole core skeleton were conducted according to the current SAR data of PZM21 (2a) and its derivatives. New derivatives were biologically evaluated for their agonistic effects on cyclic adenosine monophosphate(cAMP) levels for the Gi pathway and β-arrestin recruitment in MOR/κ-opioid receptor/δ opioid receptor. An optimized selective Gi-biased agonist, Compound 17a, was discovered with potent cAMP inhibitory activities, with a 50% efficacy concentration valueof 87.1 nM and no activity in the MOR β-arrestin pathway and other subtypes. The in vivo pain relief efficacy of Compound 17a was confirmed in a dose-dependent manner with spinal nerve ligation and cisplatin-induced peripheral neuropathy rodent neuropathic pain models.

Rational Design of Potent Activators and Inhibitors of the Enterococcus faecalis Fsr Quorum Sensing Circuit.

The increasing rate of resistance development to conventional antibiotics by bacteria necessitates the identification of alternative treatment possibilities that can reduce the ability of bacteria to adapt. Enterococcus faecalis remains the leading cause of clinical enterococci infections and has exhibited quorum sensing (QS)-dependent pathogenicity. Here, we report the development of macrocyclic peptide-based activators and inhibitors of the E. faecalis Fsr QS circuitry. To this end, we developed, optimized, and compared three synthetic routes for lactone-containing macrocyclic peptide scaffolds. We then utilized previous and current structure-activity relationship (SAR) insights of the native QS signaling peptide to rationally design the most potent activators and inhibitors of the Fsr QS circuitry identified to date. The application of these peptides could provide a means to attenuate the pathogenicity of E. faecalis without introducing significant selective pressure on the bacteria to develop resistance.

Chemical Approaches to Inhibiting the Hepatitis B Virus Ribonuclease H

Hepatitis B virus (HBV) chronically infects >250 million people and kills nearly a million annually, and current antivirals cannot clear the infection or adequately suppress disease. The virus replicates by reverse transcription, and the dominant antiviral drugs are nucleos(t)ide analogs that target the viral reverse transcriptase. We are developing antivirals targeting the other essential viral enzymatic activity, the ribonuclease H (RNaseH). HBV RNaseH inhibitors with efficacies in the low micromolar to nanomolar range against viral replication in culture have been identified in the α-hydroxytropolone and hydroxyimide chemotypes. Here, we review the promise of RNaseH inhibitors, their current structure-activity relationships, and challenges to optimizing the inhibitors into leads for clinical assessment.

Revised structure activity parameters derived from new rate coefficient determinations for the reactions of chlorine atoms with a series of seven ketones at 290 K and 1 atm

Rate coefficients of Cl atom reactions with several ketones have been investigated at 298K and 1atm using relative rate methods, monitoring substrates with both GC and FTIR and with two reference compounds. The following rate coefficients (1010k/cm3 molecule−1s−1) were obtained: k(2-pentanone)=(1.08±0.05), k(3-pentanone)=(0.89±0.12), k(3-methyl-2-butanone)=(0.68±0.06), k(4-methyl-2-pentanone)=(1.10±0.10), k(5-methyl-2-hexanone)=(1.65±0.14), k(3-methyl-2-pentanone)=(0.94±0.10) and k(3,3-dimethyl-2-butanone)=(0.48±0.05). The results are discussed in terms of Cl reactivity trends and existing literature. k(3-methyl-2-pentanone) and k(3,3-dimethyl-2-butanone) are poorly predicted with current structure activity relationships and revised parameters are proposed. In regions of high [Cl], these reactions can significantly reduce the fraction of ketones reaching the free troposphere.

Large-scale prediction of drug–target interactions using protein sequences and drug topological structures

The identification of interactions between drugs and target proteins plays a key role in the process of genomic drug discovery. It is both consuming and costly to determine drug–target interactions by experiments alone. Therefore, there is an urgent need to develop new in silico prediction approaches capable of identifying these potential drug–target interactions in a timely manner. In this article, we aim at extending current structure–activity relationship (SAR) methodology to fulfill such requirements. In some sense, a drug–target interaction can be regarded as an event or property triggered by many influence factors from drugs and target proteins. Thus, each interaction pair can be represented theoretically by using these factors which are based on the structural and physicochemical properties simultaneously from drugs and proteins. To realize this, drug molecules are encoded with MACCS substructure fingerings representing existence of certain functional groups or fragments; and proteins are encoded with some biochemical and physicochemical properties. Four classes of drug–target interaction networks in humans involving enzymes, ion channels, G-protein-coupled receptors (GPCRs) and nuclear receptors, are independently used for establishing predictive models with support vector machines (SVMs). The SVM models gave prediction accuracy of 90.31%, 88.91%, 84.68% and 83.74% for four datasets, respectively. In conclusion, the results demonstrate the ability of our proposed method to predict the drug–target interactions, and show a general compatibility between the new scheme and current SAR methodology. They open the way to a host of new investigations on the diversity analysis and prediction of drug–target interactions.

From fungus to pharmaceuticals – the chemistry of statins

It has long been recognised that high circulating levels of cholesterol are associated with the development of cardiovascular disease. With the discovery of the cholesterol biosynthetic pathway in 1950, it was soon realised that blockade of key conversions in this pathway may provide useful therapeutic targets for the management of hypercholesterolaemia. In the 1970s the first useful inhibitors of cholesterol biosynthesis were isolated, and paved the way for what would become a multimillion dollar pharmaceutical industry. Modern-day statins are incredibly effective hypolipidaemic agents, interrupting cholesterol biosynthesis at the rate-limiting step through a competitive inhibition mechanism. These compounds' structures interact with key amino acid residues through a variety of defined bonding interactions, and by understanding how these interactions form, better, and safer, hypolipidaemic agents were found. This review describes the historical development of statins and brings us up-to-date with current structure-activity relationships between statins and their target enzyme.

Discovery of MAO-B Inhibitors - Present Status and Future Directions Part I: Oxygen Heterocycles and Analogs

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The role of monoamine oxidase (MAO) inhibitors has expanded in the PD treatment. The present review will summarize the current structureactivity relationship information available on MAOs inhibitors of unrelated families of compounds of oxygen heterocyclic type based on coumarin, chromone and chalcone scaffolds. As the current hitting-one-target therapeutic strategy has been proved to be quite inefficient in PD, this review will also discuss about the development of multi-target drugs, in which MAO inhibition plays a counter-part, as a novel and promising treatment approach for PD.

Kinetic Study of Gas-Phase Reactions of OH and NO3Radicals and O3with iso-Butyl andtert-Butyl Vinyl Ethers

Using a relative rate technique, kinetic studies on the gas-phase reactions of OH radicals, ozone, and NO(3) radicals with iso-butyl vinyl ether (iBVE) and tert-butyl vinyl ether (tBVE) have been performed in a 405 L Duran glass chamber at (298 ± 3) K and atmospheric pressure (750 ± 10 Torr) in synthetic air using in situ FTIR spectroscopy to monitor the reactants. The following rate coefficients (in units of cm(3) molecule(-1) s(-1)) have been obtained: (1.08 ± 0.23) × 10(-10) and (1.25 ± 0.32) × 10(-10) for the reactions of OH with iBVE and tBVE, respectively; (2.85 ± 0.62) × 10(-16) and (5.30 ± 1.07) × 10(-16) for the ozonolysis of iBVE and tBVE, respectively; and (1.99 ± 0.56) × 10(-12) and (4.81 ± 1.01) × 10(-12) for the reactions of NO(3) with iBVE and tBVE, respectively. The rate coefficients for the NO(3) reactions are first-time determinations. The measured rate coefficients are compared with estimates using current structure activity relationship (SAR) methods and the effects of the alkoxy group on the gas-phase reactivity of the alkyl vinyl ethers toward the oxidants are compared and discussed. In addition, estimates of the tropospheric lifetimes of iBVE and tBVE with respect to their reactions with OH, ozone, and NO(3) for typical OH radical, ozone, and NO(3) radical concentrations are made, and their relevance for the environmental fate of compounds is considered.

Structure of Ddn, the Deazaflavin-Dependent Nitroreductase from Mycobacterium tuberculosis Involved in Bioreductive Activation of PA-824

SummaryTuberculosis continues to be a global health threat, making bicyclic nitroimidazoles an important new class of therapeutics. A deazaflavin-dependent nitroreductase (Ddn) from Mycobacterium tuberculosis catalyzes the reduction of nitroimidazoles such as PA-824, resulting in intracellular release of lethal reactive nitrogen species. The N-terminal 30 residues of Ddn are functionally important but are flexible or access multiple conformations, preventing structural characterization of the full-length, enzymatically active enzyme. Several structures were determined of a truncated, inactive Ddn protein core with and without bound F420 deazaflavin coenzyme as well as of a catalytically competent homolog from Nocardia farcinica. Mutagenesis studies based on these structures identified residues important for binding of F420 and PA-824. The proposed orientation of the tail of PA-824 toward the N terminus of Ddn is consistent with current structure-activity relationship data.

Further structurally constrained analogues of cis-(6-benzhydrylpiperidin-3-yl)benzylamine with elucidation of bioactive conformation: discovery of 1,4-diazabicyclo[3.3.1]nonane derivatives and evaluation of their biological properties for the monoamine transporters.

Our structure-activity relationship (SAR) study on piperidine analogues for monoamine transporters led to the development of a series of 3,6-disubstituted piperidine derivatives, structurally constrained versions of flexible piperidine analogues, with preferential affinity for the dopamine transporter (DAT). In our attempt to further rigidify this structure to study influence of rigidity on binding and in vivo activity, we have developed a series of 4,8-disubstituted 1,4-diazabicyclo[3.3.1]nonane derivatives. All synthesized derivatives were tested for their affinity at the DAT, serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in competing for the binding of [(3)H]WIN 35, 428, [(3)H]citalopram, and [(3)H]nisoxetine, respectively. Selected compounds were also tested for their ability to inhibit uptake of [(3)H]DA. The SAR study led to the discovery of a potent lead compound (-)-S,S-10c which exhibited high affinity and selectivity for the DAT (IC(50) = 22.5 nM; SERT/DAT = 384 and NET/DAT > 444). It is interesting to note that both (-)-10c and the lead compound from the 3,6-disubstituted series (-)-2 exhibited highest activity in their (S,S) isomer indicating similar requirement of regiospecificity for maximum interaction. Overall, our current SAR results corresponded well with the results from less constrained 3,6-disubstituted versions of these molecules albeit the former class exhibited more stringent requirement in molecular structure for activity. However, the potent compounds in the current series exhibited greater selectivity for the DAT compared to their corresponding lesser constrained 3,6-disubstituted versions indicating an effect of rigidity in selective interaction with the transporter proteins. In an effort to elucidate the bioactive conformational structure of the lead molecules in the current and the 3,6-disubstituted series, a preliminary molecular modeling study was carried out where the most rigid derivative (-)-10c was used as a template structure. Compounds (-)-2 and (-)-10c exhibited stimulant activity in locomotor tests in mice in which (-)-2 exhibited a slower onset and longer duration of action compared to (-)-10c. Both compounds occasioned complete cocaine-like responding in mice trained to discriminate 10 mg/kg ip cocaine from vehicle.

Enhanced H-atom abstraction from pinonaldehyde, pinonic acid, pinic acid, and related compounds: theoretical study of C–H bond strengths

The experimentally observed rate of the pinonaldehyde + OH reaction is substantially higher than expected from established structure activity relationships (SARs). In this study the C–H bond strengths in pinonaldehyde and in related, structurally similar compounds are investigated theoretically using B3LYP-DFT/6-31G(d,p). We find bond strengths in agreement with the literature values for smaller reference compounds, except for the abstraction of hydrogens from the exocyclic CH2 group, which has a significantly lower bond strength due to strain-enhanced hyperconjugation. The rate constant for H-abstraction from this group in pinonaldehyde is estimated at 8 × 10−12 cm3 molecule−1 s−1. The C–H bond strengths of the two tertiary hydrogens on the carbons in the four-membered ring are found to have normal values, in contrast to the high values for secondary hydrogens in (substituted) cyclobutane(s); the summed rate coefficient for abstracting these two tertiary hydrogens in pinonaldehyde is estimated at 5 × 10−12 cm3 molecule−1 s−1. The resulting total rate constant estimated for H-abstraction from pinonaldehyde by OH is 3.5 × 10−11 cm3 molecule−1 s−1, with a ca. 59∶23∶14 ratio of aldehyde-H, exocyclic-CH2-hydrogen, and tertiary-H abstraction. This predicted branching has important implications for the ultimate product yields in the OH-initiated atmospheric oxidation of pinonaldehyde. Similar effects are found for pinonic acid, pinic acid and related compounds, and are predicted to entail rate constants of the gas-phase reactions of these compounds with OH radicals of 1 × 10−11 cm3 molecule−1 s−1, i.e. 3 times higher than expected from the current standard SAR.

Structure-activity relationship studies of 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine derivatives and their N-analogues: evaluation of O-and N-analogues and their binding to monoamine transporters.

In our effort to develop a pharmacotherapy for the treatment of cocaine addiction, we embarked on synthesizing novel molecules targeting the dopamine transporter (DAT) molecule in the brain as DAT has been implicated strongly in the reinforcing effect of cocaine. Our previously developed DAT-selective piperidine analogue, 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine, was the basis for our current structure-activity relationship (SAR) studies exploring the significance of the contribution of the benzhydryl O- and N-atoms in these molecules in interacting with the DAT. Thus, we replaced the benzhydryl O-atom with an N-atom, altered the location of the benzhydryl N-atom to an adjacent position, and in one other occasion converted the benzhydryl O-ether linkage into an oxime-type derivative. Furthermore, we also evaluated the important contribution of the piperidine N-atom to binding by altering its pK(a) value chemically. Novel analogues were tested for potency in inhibiting [3H]WIN 35,428, [3H]citalopram, and [3H]nisoxetine binding at the DAT, serotonin transporter (SERT), and norepinepherine transporter (NET). [3H]DA was used to measure DA reuptake inhibition. The results indicated that the benzhydryl O- and N-atoms are exchangeable for the most part. On the other hand, an enhanced interaction with the SERT was observed when the benzhydryl N-atom moved to an adjacent position (21a; DAT (IC(50)) = 19.7, SERT (IC(50)) = 137 nM, NET (IC(50)) = 1111 nM). In either cases, further alkylation of the N-atom reduced the activity for the transporter. The presence of a powerful electron-withdrawing cyano group in compound 5d expectedly produced the most potent and selective ligand for the DAT (DAT (IC(50)) = 3.7 nM, DAT/SERT = 615). Selected compounds were further analyzed in the dopamine reuptake inhibition assay. Preliminary behavioral assessment of some of the selected compounds in mice indicated that these compounds are much less stimulating when compared with cocaine at comparable doses. In drug-discrimination studies these selected compounds incompletely generalized from the cocaine stimulus in mice trained to discriminate 10 mg/kg cocaine from vehicle.

Computer-assisted studies of molecular structure-biological activity relationships.

Computer-assisted methods can be used to investigate the relationships between the molecular structures of compounds and their biological activity. A number of approaches have been reported in the literature, including correlations of activity with substituent constants, conformational analysis and display, quantum mechanical methods, and methods relying on discriminant development and pattern-recognition techniques. Application areas for this technology include drug design, agricultural chemical design, and studies of chemical toxicity and genetic toxicity (mutagenic or carcinogenic potential). These structure-activity methods are introduced, and citations are given. Several current structure-activity relationship (SAR) studies using pattern recognition are presented as examples of typical projects that are feasible with this approach. These include the investigation of a set of 122 antiinflammatory steroids, a study of 153 retinoids for cancer prevention, and a study of chemicals that have been tested in a sister chromatid exchange mutagen screen.