Comparison on effect of hydrophobicity on the antibacterial and antifungal activities of α-helical antimicrobial peptides

HPRP-A1, a 15-mer α-helical cationic peptide, was derived from N-terminus of ribosomal protein L1 (RpL1) of Helicobacter pylori. In this study, HPRP-A1 was used as a framework to obtain a series of peptide analogs with different hydrophobicity by single amino acid substitutions in the center of nonpolar face of the amphipathic helix in order to systematically study the effect of hydrophobicity on biological activities of -helical antimicrobial peptides. Hydrophobicity and net charge of peptides played key roles in the biological activities of these peptide analogs; HPRP-A1 and peptide analogs with relative higher hydrophobicity exerted broad spectrum antimicrobial activity against Gram-negative bacteria, Gram-positive bacteria and pathogenic fungi, but also showed stronger hemolytic activity; the change of hydrophobicity and net charge of peptides had similar effects with close trend and extent on antibacterial activities and antifungal activities. This indicated that there were certain correlations between the antibacterial mode of action and the antifungal mode of action of these peptides in this study. The peptides exhibited antimicrobial specificity for bacteria and fungi, which provided potentials to develop new antimicrobial drugs for clinical practices.     

The enantiomers of syn-2,3-difluoro-4-aminobutyric acid elicit opposite responses at the GABA(C) receptor

The conformational behaviour and GABA receptor activity of the different stereoisomers of 2,3-difluoro-4-aminobutyric acid are described. Two enantiomeric GABA(C)-active ligands are identified, one of which is an agonist while the other is an antagonist. The results support an existing QSAR model of the bioactive geometry of GABA at GABA(C).     

Insight into crucial inhibitor–enzyme interaction of arylamides as novel direct inhibitors of the enoyl ACP reductase (InhA) from Mycobacterium tuberculosis: computer-aided molecular design

Abstract  

The enoyl ACP reductase enzyme (InhA) involved in the type II fatty acid biosynthesis pathway of Mycobacterium tuberculosis is an attractive target enzyme for antitubercular drug development. Arylamide derivatives are a novel class of InhA inhibitors used to overcome the drug-resistance problem of isoniazid, the frontline drug for tuberculosis treatment. Their remarkable property of inhibiting the InhA enzyme directly without requiring any coenzyme, makes them especially appropriate for the design of new antibacterials. In order to find a sound binding conformation for the different arylamide analogs, molecular docking experiments were performed with subsequent QSAR investigations. The X-ray conformation of one arylamide within its cocrystallized complex with InhA was used as a starting conformation for the docking experiments. The results thus obtained are perfectly consistent (rmsd = 0.73 ?) with the results from X-ray analysis. A thorough investigation of the arylamide binding modes with InhA provided ample information about structural requirements for appropriate inhibitor–enzyme interactions. Three different QSAR models were established using two three-dimensional (CoMFA and CoMSIA) and one two-dimensional (HQSAR) techniques. With statistically ensured models, the QSAR results obtained had high correlation coefficients between molecular structure properties of 28 arylamide derivatives and their biological activity. Molecular fragment contributions to the biological activity of arylamides could be obtained from the HQSAR model. Finally, a graphic interpretation designed in different contour maps provided coincident information about the ligand–receptor interaction thus offering guidelines for syntheses of novel analogs with enhanced biological activity.     

Possible allosteric interactions of monoindazole-substituted P2 cyclic urea analogues with wild-type and mutant HIV-1 protease

Our ongoing efforts to understand the difference in the binding pattern of HIV-1 protease inhibitor (HIVPI) with the wild-type and mutant HIV-1 protease (HIVPR) and to provide mechanistic insight are continued further. We report here the results of a recent quantitative structure-activity relationship (QSAR) study on monoindazole-substituted P2 analogues of cyclic urea HIVPIs. The QSAR models revealed an inverted parabolic relationship between biological activity and calculated molar refractivity (CMR). That is, biological activity first decreases with increase in CMR and at a certain minimum point (inversion point) it suddenly changes and increases with further increase in CMR. CMR is a measure of volume-dependent-polarizability and is an indication of the polar interactions between ligand and receptor. The results seem to be best rationalized by larger molecules inducing a change in a receptor unit that allows for a new mode of interaction. Similar QSAR models were also observed for the biological activity of these molecules tested against a panel of mutant viruses including mutant strains with single amino acid substitution (I84V), double amino acid substitutions (I84V/V82F), and multiple amino acid changes corresponding to mutations observed in clinical isolates of patients treated with Ritonavir((R)). Interestingly the inversion points for these mutant strains were found larger than for wild-type. The subtle but significant difference in the inversion point indicates change in the shape and size of the binding pocket. Earlier QSAR studies have shown that the correlation of biological activity with an inverted parabola is an indicative of the 'allosteric interaction' of the ligands with the receptor. This report presents a detail analysis of these observations.     

Insight into Gentisic Acid Antidiabetic Potential Using In Vitro and In Silico Approaches

Numerous scientific studies have confirmed the beneficial therapeutic effects of phenolic acids. Among them gentisic acid (GA), a phenolic acid extensively found in many fruit and vegetables has been associated with an enormous confirmed health benefit. The present study aims to evaluate the antidiabetic potential of gentisic acid and highlight its mechanisms of action following in silico and in vitro approaches. The in silico study was intended to predict the interaction of GA with eight different receptors highly involved in the management and complications of diabetes (dipeptidyl-peptidase 4 (DPP4), protein tyrosine phosphatase 1B (PTP1B), free fatty acid receptor 1 (FFAR1), aldose reductase (AldR), glycogen phosphorylase (GP), α-amylase, peroxisome proliferator-activated receptor gamma (PPAR-γ) and α-glucosidase), while the in vitro study studied the potential inhibitory effect of GA against α-amylase and α-glucosidase. The results indicate that GA interacted moderately with most of the receptors and had a moderate inhibitory activity during the in vitro tests. The study therefore encourages further in vivo studies to confirm the given results.     

Structure-activity relationships of dopamine- and norepinephrine-uptake inhibitors

Quantitative structure-activity relationship (QSAR) analysis of 3-phenyl-1-indanamines, 1-amino-4-aryltetralins, and 6-phenylpyrrolo[2,1-a] isoquinolines has been performed for catecholamine-uptake inhibition activities. Similar equations were obtained for these series of congeners indicating a common tendency that the increase in hydrophobicity of the substituents on the primary phenyl ring (ring C) enhances the activity, and the important aromatic ring which interacts with the receptor is this ring C. It was also indicated that the effect of the introduction of the second N-methyl group differs depending on the series of congeners. These results were used to characterize a binding model for a pharmacophore, which comprised a phenyl ring and a basic nitrogen. This model defined the necessary three-dimensional features leading to the uptake inhibition, and degree of fitness with this model predicted the strength of the activity. Furthermore, it appeared likely that a substituent existing in a specific region of the inhibitor molecule causes a steric hindrance with the receptor site and reduces the activity.     

螺旋型抗菌肽的疏水性对抗细菌与抗真菌活性的影响比较

α-螺旋型多肽HPRP-A1由15个氨基酸残基组成,来源于幽门螺杆菌核糖体蛋白L1的N端.本研究以HPRP-A1为模板,在其非极性面中心通过单个氨基酸定点取代的方法,形成一系列疏水性不同的多肽类似物,系统地研究疏水性对α-螺旋型多肽生物活性的影响.结果显示,多肽疏水性及所带净电荷对多肽生物活性起着重要的作用;HPRP-A1及疏水性相对较高的多肽类似物具有较好的广谱抗菌活性（包括革兰氏阳性菌、革兰氏阴性菌及真菌）,但也有相对较高的溶血活性;多肽的疏水性与所带净电荷的变化对多肽抗细菌活性与抗真菌活性所产生的影响有着相似的变化趋势和程度.这意味着多肽与细菌的作用机制和多肽与真菌的作用机制存在一定的相关性.多肽对细菌和真菌的抗菌活性存在特异性,为设计出具有临床应用前景的抗菌肽药物奠定了基础.     

Characterization of the Synergistic Effect between Ligands of Opioid and Free Fatty Acid Receptors in the Mouse Model of Colitis

Background: Recent studies suggest that lipids, including free fatty acids (FFAs), are necessary for proper μ opioid receptor (MOR) binding and that activation of opioid receptors (ORs) improves intestinal inflammation. The objective of the study was to investigate a possible interaction between the ORs and FFA receptors (FFARs) ligands in the colitis. Methods: The potential synergistic effect of ORs and FFARs ligands was evaluated using mouse model of acute colitis induced by dextran sulfate sodium (DSS, 4%). Compounds were injected intraperitoneally (i.p.) once or twice daily at the doses of 0.01 or 0.02 mg/kg body weight (BW) (DAMGO—an MOR agonist), 0.3 mg/kg BW (DPDPE—a δ OR (DOR) agonist) and 1 mg/kg BW (naloxone—a non-selective OR antagonist, GLPG 0974—a FFAR2 antagonist, GSK 137647—a FFAR4 agonist and AH 7614—a FFAR4 antagonist) for 4 days. Results: Myeloperoxidase (MPO) activity was significantly decreased after DAMGO (0.02 mg/kg BW) and GSK 137647 (1 mg/kg BW) administration and co-administration as compared to DSS group. Conclusions: Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed.     

Prediction of anti-HIV activity and cytotoxicity of pyrimidinyl and triazinyl amines: A QSAR study

A QSAR study on a series of pyrimidinyl and triazinyl amines was performed to explore the physico-chemical parameters responsible for their anti-HIV activity and cytotoxicity. Physico-chemical parameters were calculated using WIN CAChe 6.1. Stepwise multiple linear regression analysis was carried out to derive QSAR models which were further evaluated for statistical significance and predictive power by internal and external validation. The selected best QSAR models showed correlation coefficient R of 0.914 and 0.901, and cross-validated squared correlation coefficient Q ² of 0.685 and 0.691 for anti-HIV activity and cytotoxicity, respectively. The developed significant QSAR model indicates that hydrophobicity of the whole molecule plays an important role in the anti-HIV activity and cytotoxicity of pyrimidinyl and triazinyl amine derivatives. When hydrophobicity is increased, anti-HIV activity of the present series of compounds is decreased leading to high cytotoxicity.     

Quantitative structure-activity relationship study of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)guanidines as potent Na/H exchange inhibitors

We have previously reported that N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-car bonyl)guanidine (4b) methanesulfonate salt (KB-R9032) is a potent and highly water-soluble Na/H exchange inhibitor. In a series of studies on Na/H exchange inhibitors, we designed and synthesized N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)guanidines (5) as more potent inhibitors with high water-solubility. The design strategy for 5 was based on a quantitative structure-activity relationship (QSAR) study, involving the proportional relationship between the biological activity and hydrophobicity of the ring structure of compounds 4. As expected, compounds 5 showed more potent activity than 4. It was found by using the QSAR analysis that 5 were about five-fold more potent than 4. The increase in potency of compounds 5 well agreed with our previous QSAR analysis result. The most potent derivative was the methanesulfonate salt 5d of the 4-isopropyl derivative (IC50=0.0091 microM). And in addition to the in vitro study, 5d showed significant protective activity against a rat acute myocardial infraction model.     

Further exploration of antimicrobial ketodihydronicotinic acid derivatives by multiple parallel syntheses

A synthetic reexamination of a series of ketodihydronicotinic acid class antibacterial agents was undertaken in an attempt to improve their therapeutic potential. A convenient new synthesis was developed involving hetero Diels-Alder chemistry producing 74 new analogs in a multiple parallel synthetic manner and these were examined in vitro for their antimicrobial potential. Several compounds demonstrated significant broad-spectrum activity against clinically derived bacterial strains but previously known 1-(2,4-difluorophenyl)-6-(4-dimethylaminophenyl)-4-pyridone-3-carboxylic acid (7) remained the most potent compound in this class. Cross-resistance with ciprofloxacin supported a commonality of mode of action. Permiabilization of Escherichia coli cells by polymyxin B significantly enhanced potency with these agents suggesting that poor cellular uptake was primarily responsible for the disappointing activity against bacteria that some of the analogs exhibited.     

疏水双功能介孔固体酸的合成及其在乙酸乙酯酯化反应中的应用

通过水热合成法一步合成了具有不同疏水基团－CH₃ 、－(CH₃)₂ 和－(CH₃)₃的双功能介孔固体酸SBA-15-SO₃H－(CH₃)_x催化剂。通过X射线粉末衍射(XRD)、N₂吸脱附、元素分析等方法对催化剂进行了表征,并在乙酸乙酯酯化反应中进行催化性能评价。结果表明,随着疏水前驱体中甲基数的增加,样品的疏水性增强。SBA-15-SO₃H-(CH₃)_x催化剂的催化活性随着疏水性的增强而提高,而具有较强疏水性的材料SBA-15-SO₃H-(CH₃)₃在反应中具有较高的催化性能。以SBA-15-SO₃H-(CH₃)₃为催化剂,酯化反应的最优条件为：温度为120℃,乙酸与乙醇摩尔比为4∶1,催化剂质量分数为1 %,反应时间为1h。在此条件下,乙醇的转化率和乙酸乙酯的选择性分别为93%和100%。     

蜂毒肽C末端片段的反序肽的抗菌活性和溶血活性

设计并合成了具有不同碱性氨基酸残基数和不同疏水性片段链长的基于Mel(12~26)的系列反序肽类似物.结果表明,反序肽的正电荷和疏水性对于抑菌活性都很重要,N端至少保留3个碱性氨基酸(正电荷>4)和C端的疏水性片段的链长至少为8个氨基酸残基的类似物具有较高的抑菌活性,具有较大的抑菌活性的最小反序肽类似物为具有11个氨基酸残基的RetroMel(13~23).这些反序肽的溶血活性都很小.     

The definition of the molecular structure for potential anti-malaria agents by the Monte Carlo method

A series of 53 endochin analogs (4(1-H)-quinolone derivatives) with anti-malarial activity against the clinically relevant multidrug resistant malarial strain TM-90-C2B has been studied. The CORAL (http://www.insilico.eu/coral) software has been used as a tool to build up the quantitative structure–activity relationships (QSAR) for the anti-malaria activity. The QSAR models were calculated with the representation of the molecular structure by simplified molecular input-line entry system and by the molecular graph of atomic orbitals. The method for splitting data into the sub-training set, the calibration set, the test set, and the validation set is suggested. Three various splits were examined. Statistical quality of models for the validation sets (which are not involved in the building up models) is good. Structural indicators (alerts) for increase and decrease of the anti-malaria activity are defined.     

Synthesis and anti-hepatitis B virus activity of new pyrimidine peptide nucleic acid analogs

A series of 4-methylsulfanylpyrimidin-2(1H)-one peptide nucleic acid analogs were synthesized and tested for their antiviral activity against hepatitis B virus. Plaque reduction infectivity assay was used to determine the virus count reduction as a result of treatment with tested compounds.     

Theoretical studies on opioid receptors and ligands. I. Molecular modeling and QSAR studies on the interaction mechanism of fentanyl analogs binding to μ‐opioid receptor

Based on our previous result of the three‐dimensional model of the μ‐opioid receptor, binding conformations of 13 fentanyl analogs and three‐dimensional structures for the complexs of these analogs with μ‐opioid receptor were constructed employing the molecular modeling method and our binding conformation search program for ligands (BCSPL). Energetic calculation and quantitative structure–activity relationship (QSAR) analysis indicated a good correlation between the calculated binding energies of fentanyl analogs and their binding affinities, pK_i's and pK's, and analgesic activities, − log ED₅₀'s. Based on the three‐dimensional models, the possible interaction mechanism of fentanyl analogs with μ‐opioid receptor can be illustrated and the available structure–activity relationship of these analgesic agents can be explained reasonably. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 78: 285–293, 2000     

DAPY类化合物抑制野生型HIV-1活性的QSAR研究

应用分子力学、半经验量子化学RM1方法优化了32个抗野生型HIV-1病毒毒株的二芳基嘧啶类(DAPYs)化合物分子结构,从分子构象模型中提取了多种参数并结合疏水性参数与指示性参数建立QSAR多元线性回归方程.回归方程显示:分子体积V的增大会降低其抑制活性,而左苯环与嘧啶环间二面角θ增大可以提高抑制活性.同时指示性参数I表明左苯环CN基团加入可以明显增加抑制活性,嘧啶环上R1位置苯基与硝基的加入可以极大降低抑制活性.