Three-dimensional Quantitative Structure-activity Relationship Models Research Articles

Novel Cinnamic Acid Derivatives Containing the 1,3,4-Oxadiazole Moiety: Design, Synthesis, Antibacterial Activities, and Mechanisms.

There is a lack of effective antibacterial agents against rice bacterial leaf streak and leaf blight. Cinnamic acid derivatives containing the 1,3,4-oxadiazole moiety were synthesized, and their antibacterial activities against Xanthomonas oryzae pv. oryzicola (Xoc) and X. oryzae pv. oryzae (Xoo) were evaluated. Based on the three-dimensional quantitative structure-activity relationship (3D-QSAR) model, compound 31 with better antibacterial activity against Xoc was designed and synthesized, and the 50% effective concentration (EC50) value was 0.2 mg/L. The curative and protective activities of compound 31 against rice bacterial leaf streak at 100 mg/L were 39.5 and 35.4%, respectively, which were higher than those of thiodiazole copper (28.4 and 20.7%, respectively). The antibacterial activity of compound 31 against rice bacterial leaf streak is closely associated with the activity of related defensive enzymes and the increase in glutathione metabolism.

Computational Atom-based Three-Dimensional Quantitative Structure-Activity Relationship (3D QSAR) Model for Predicting Anti-Dengue Agents

Dengue fever is a viral infection spread by the female mosquito Aedes aegypti. It is a virus spread by mosquitoes found all over the tropics with risk levels varying depending on rainfall, relative humidity, temperature and urbanization. There are no specific medications that can be used to treat the condition. The development of possible bioactive ligands to combat Dengue fever before it becomes a pandemic is a global priority. Few studies on building three-dimensional quantitative structure-activity relationship (3D QSAR) models for anti-dengue agents have been reported. Thus, we aimed at building a statistically validated atom-based 3D-QSAR model using bioactive ligands reported to possess significant anti-dengue properties. In this study, the Schrodinger PhaseTM atom-based 3D QSAR model was developed and was validated using known anti-dengue properties as ligand data. This model was also tested to see if there was a link between structural characteristics and anti-dengue activity of a series of 3-acyl-indole derivatives. The established 3D QSAR model has strong predictive capacity and is statistically significant [Model: R2 Training Set = 0.93, Q2 (R2 Test Set) = 0.72]. In addition, the pharmacophore characteristics essential for the reported anti-dengue properties were explored using combined effects contour maps (coloured contour maps: blue: positive potential and red: negative potential) of the model. In the pathway of anti-dengue drug development, the model could be included as a virtual screening method to predict novel hits.

In silico analysis of 3D QSAR and Molecular Docking studies to discover new thiadiazole-thiazolone derivatives as mitotic kinesin Eg5 inhibition

A series of twenty one thiadiazole-thiazolone derivatives which is a class of highly potent human mitotic kinesin Eg5 inhibitor reported from published article were studied through a series of computer-aided drug design processes such as three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) and Surflex-docking method using 17 compounds as training set. Both models showed good statistical quality and satisfying predictive ability (Q 2 = 0.617 and R 2 =0.919 for CoMFA ) and (Q 2 = 0.638 and R 2 =0.919 for CoMSIA ). The aim of this study was to explore 3D-QSAR approaches to propose new thiadiazole-thiazolone derivatives as Eg5 inhibitors for human mitotic kinesin. The CoMFA/CoMSIA contour maps were generated to provide the information about regions where the activity might be increased or decreased. Moreover, Based on the X-ray crystallized complex (PDB ID: 2UYM) molecular docking was performed on the most potent proposed Eg5 inhibitors using Surflex-dock method as an approach to investigate the stability of docked conformation and study the binding interactions in detail.

A QSAR Study of Peptidyl Vinyl Sulfone Cysteine Protease Inhibitors Using Topomer CoMFA and Molecular Docking

Background: Malaria is one of the most important infectious diseases in the world. The most severe form of malaria in humans is caused by Plasmodium falciparum. Malaria is a worldwide health problem, with 214 million new cases in 2015 and 438,000 deaths, most of which are in Africa. Therefore, there is an urgent need for novel, low-toxic, more specific inhibitors to find new antimalarial agents. A promising target for antimalarial drug design is falcipain-2, a cysteine protease from P. falciparum that has received considerable attention due to its key role in the life cycle of the parasite. Materials and Methods: Three-dimensional quantitative structure-activity relationship (3D-QSAR) models of 39 peptidyl vinyl sulfone cysteine protease inhibitors was constructed using Topomer CoMFA. Topomer Search was employed to virtually screen lead-like compounds in the ZINC database. Molecular docking was employed to further explore the binding requirements between the ligands and the receptor protein which included several hydrogen bonds between peptidyl vinyl sulfone cysteine protease inhibitors and active site residues. Results: The non-cross correlation coefficient (r2), the interaction validation coefficient (q2) and the external validation (r2 pred) were 0.902, 0.685 and 0.763, respectively. The results showed that the model not only had good estimation stability but also good prediction capability. 22 new molecules were obtained, whose predicted activity is higher than the template molecules. The results showed that the Topomer Search technology can be effectively applied to screen and design new peptidyl vinyl sulfone cysteine protease inhibitors. Molecular docking showed extensive interactions between peptidyl vinyl sulfone cysteine protease inhibitors and residues of LYS24, ASP21, LYS59, and ASP17 in the active site. Conclusion: : 39 peptidyl vinyl sulfone cysteine protease inhibitors were used in the 3D-QSAR study. Topomer CoMFA 3D-QSAR method was used to build the model, and the model was well predicted and statistically validated. The design of potent new inhibitors of cysteine protease can get useful insights from these results.

Molecular Modifications and Control of Processes to Facilitate the Synergistic Degradation of Polybrominated Diphenyl Ethers in Soil by Plants and Microorganisms Based on Queuing Scoring Method.

In this paper, a combination of modification of the source and regulation of the process was used to control the degradation of PBDEs by plants and microorganisms. First, the key proteins that can degrade PBDEs in plants and microorganisms were searched in the PDB (Protein Data Bank), and a molecular docking method was used to characterize the binding ability of PBDEs to two key proteins. Next, the synergistic binding ability of PBDEs to the two key proteins was evaluated based on the queuing integral method. Based on this, three groups of three-dimensional quantitative structure-activity relationship (3D-QSAR) models of plant-microbial synergistic degradation were constructed. A total of 30 PBDE derivatives were designed using BDE-3 as the template molecule. Among them, the effect on the synergistic degradation of six PBDE derivatives, including BDE-3-4, was significantly improved (increased by more than 20%) and the environment-friendly and functional evaluation parameters were improved. Subsequently, studies on the synergistic degradation of PBDEs and their derivatives by plants and microorganisms, based on the molecular docking method, found that the addition of lipophilic groups by modification is beneficial to enhance the efficiency of synergistic degradation of PBDEs by plants and microorganisms. Further, while docking PBDEs, the number of amino acids was increased and the binding bond length was decreased compared to the template molecules, i.e., PBDE derivatives could be naturally degraded more efficiently. Finally, molecular dynamics simulation by the Taguchi orthogonal experiment and a full factorial experimental design were used to simulate the effects of various regulatory schemes on the synergistic degradation of PBDEs by plants and microorganisms. It was found that optimal regulation occurred when the appropriate amount of carbon dioxide was supplied to the plant and microbial systems. This paper aims to provide theoretical support for enhancing the synergistic degradation of PBDEs by plants and microorganisms in e-waste dismantling sites and their surrounding polluted areas, as well as, realize the research and development of green alternatives to PBDE flame retardants.

VHTS and 3D-QSAR for the Identification of Novel Phyto-inhibitors of Farnesyltransferase: Validation of Ascorbic Acid inhibition of Farnesyltransferase in an Animal Model of Breast Cancer.

Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of attention in anti-cancer research over the past. In this study, phytochemicals from Curcuma longa L., Taraxacum officinale, and Spondias mombin plants were screened for their inhibitory potentials on the human farnesyltransferase. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model for the inhibition of farnesyltransferase was generated and the inhibition of farnesyltransferase by the hit, ascorbic acid was validated in an animal model of breast cancer. The lead compound, ascorbic acid makes extensive hydrogen bond interactions with key residues, lys-353, tyr-300, gly-290, leu-290 within the active site of farnesyltransferase. It downregulated the expression of FNTA mRNA in an animal model of breast cancer. The 3D-QSAR generated herein is robust, thoroughly validated, and should be employed in the pipelining of novel farnesyltransferase inhibitors. Ascorbic acid demonstrates its anticancer potentials through the inhibition of farnesyltransferase.

A combined structure-based pharmacophore modeling and 3D-QSAR study on a series of N-heterocyclic scaffolds to screen novel antagonists as human DHFR inhibitors

Dihydrofolate reductase (DHFR) is an essential enzyme that participates in folate metabolism and purine and thymidylate synthesis in cell proliferation. It converts dihydrofolate (DHF) to tetrahydrofolate (THF) in the presence of nicotinamide adenine dinucleotide phosphate (NADPH). This enzyme is found within all organisms adjusting the cellular level of THF. Negligible DHFR activity leads to a deficiency of THF and cell death. This trait is used to inhibit the cancer cells. DHFR has been extensively studied as the therapeutic target for cancer treatment. Accordingly, there is an urgent need for the identification and development of novel effective inhibitors with higher selectivity, lower toxicity, and better potency than currently available drugs. Hence, we aimed to identify new compounds by utilizing the alignment-independent three-dimensional quantitative structure-activity relationship (3D-QSAR) and structure-based pharmacophore modeling. Using the results obtained from these approaches, several antagonists have been retrieved from the virtual screening by applying some filters such as Lipinski’s rule of five. Selected compounds were then docked into the binding site of the receptor for identification of ligand-receptor interactions, binding affinity prediction, and refinement based on GoldScore fitness values. Eventually, pharmacokinetic/drug-likeness features and toxicity profiles of novel compounds were predicted and evaluated. Four hits with PubChem CIDs of 136138676, 94182663, 60219817, and 133300845 were finally proposed as new candidates with potential inhibitory activity against human DHFR.

Laboratory bioassay, greenhouse experiment and 3D-QSAR studies on berberine analogues: a search for new herbicides based on natural products.

Berberine is a herbicidal chemical that we isolated from Coptis chinensis. In continuation of our program aimed at discovering and developing natural botanical herbicides, we evaluated the herbicidal activities of 39 berberine analogues and developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model. Among these 39 analogs, the most active compounds were determined to be worenine chloride and coptisine chloride, with median inhibitory concentration (IC50 ) values on all eight tested weed species of < 10 mg L-1 . As a reference, the IC50 values of berberine on six weed species were < 10 mg L-1 . Furthermore, the results of a greenhouse experiment showed that at 10 mg L-1 , and 7 days after treatment, the effects of worenine chloride and coptisine chloride on Lemna minor and Ageratum conyzoides were significantly higher than those of glyphosate and sulcotrione. In the 3D-QSAR analysis, the electrostatic field contour map indicated that introducing an electropositive group in the N-7, C-9 and C-10 positions would potentially improve the inhibition rate. A positively charged nitrogen atom at the N-7 position was important for activity. Replacement of -OCH3 by -OH at the C-9 and C-10 positions could decrease the inhibitory activity, while the hydrophobic field contour map revealed that the hydrophobicity of the C-10 position was associated with high activity. Moreover, the hydrogen bond acceptor field contour map suggested that the existence of a hydrogen bond acceptor at the C-3 and C-9 positions might affect the inhibition rate. 3D-QSAR provided meaningful clues to the structural features of berberine analogues that will assist the design of more potent herbicidal compounds in the future. © 2020 Society of Chemical Industry.

Antioxidant activities of major tryptophyllin L peptides: A joint investigation of Gaussian-based 3D-QSAR and radical scavenging experiments.

The red tree frog Litoria rubella from Australia has been studied for several decades showing that their dorsal skin glands secrete a number of small peptides containing a Pro-Trp sequence, known as tryptophyllin L peptides. Although peptides from many genera of Australian frogs have been reported to possess a variety of biological activities, the bioactivities of this peptide family have remained to be discovered. In this study, we investigated the antioxidant potency of a number of tryptophyllin L peptides for the first time using a joint statistical and experimental approach in which predictions based on Gaussian three-dimensional quantitative structure-activity relationship (3D-QSAR) models were employed to guide an in vitro experimental investigation. Two tryptophyllin tripeptides P-W-L (OH) and P-W-L (NH2 ) were predicted to have the Trolox equivalent antioxidant capacity (TEAC) values of 0.80 and 0.87 μM Trolox/μM peptide, respectively. With those promising results, antioxidant capabilities of five tryptophyllin L peptides with the common core Pro-Trp-Leu were synthesized and subjected to 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing ability of plasma (FRAP) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) radical cation (ABTS˙+ ) radical scavenging assays. The tests indicated that all the tested tryptophyllin L peptides, noticeably S-P-W-L (OH) and F-P-W-L (NH2 ), are strong ABTS˙+ radical scavengers and moderate scavengers in the other two assays. The results, thus, suggested that the tryptophyllin L peptides are likely to be a part of the skin antioxidant system helping the frog to cope with drastic change in oxygen exposure and humidity, as they inhabit over a large area of Australia with a wide climate variation.

Synthesis, extracorporeal nephrotoxicity, and 3D-QSAR of andrographolide derivatives.

Andrographolide is a traditional Chinese medicine monomer with many pharmacological activities, but has potential nephrotoxicity. Here, we aim to investigate the relationship between modification of andrographolide structure and its nephrotoxicity. Twenty-three andrographolide derivatives were synthesized, and their structures were confirmed by 1 H-NMR and HRMS. Nephrotoxicity of these compounds against human renal tubular epithelial (HK-2) cells was evaluated using the MTT assay. The results indicated that most of them had significantly reduced nephrotoxicity, especially compounds III, V, and IXc , with IC50 values of 1,985, 1,300, and 806.9μmol/L, respectively, which were obviously superior to andrographolide (IC50 30.60μmol/L). However, compounds Ia -If (IC50 values<30μmol/L), the 14-OH derivatives of andrographolide, showed higher nephrotoxicity than that of andrographolide. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models of COMFA and COMSIA were established (COMFA: q2 =0.639, r2 =0.951; COMSIA: q2 =0.569, r2 =0.857). This model allowed proposing five new compounds with lower theoretical nephrotoxicity, which would be worthwhile to synthesize and evaluate. We believe that predicted models will help us to understand the structural modification requirements of andrographolide to reduce the nephrotoxicity, and further investigations will be needed to determine the mechanism involved in the effect of less nephrotoxic compounds.

A Modified 3D-QSAR Model Based on Ideal Point Method and Its Application in the Molecular Modification of Plasticizers with Flame Retardancy and Eco-Friendliness.

The addition of plasticizers makes plastics flammable, and thus, poses a potential risk to the environment. In previous researches, plasticizers with flame retardancy had been synthesized, but their eco-friendliness had not been tested or described. Thus, in this paper, eco-friendliness plasticizers with flame retardancy were designed based on phthalic acid esters (PAEs), which are known as common plasticizers and major plastic additives. For a comprehensive analysis, such as flammability, biotoxicity, and enrichment effects, 17 PAEs’ comprehensive evaluation values were calculated based on the ideal point method. Further, a multi-effect three-dimensional quantitative structure-activity relationship (3D-QSAR) model of PAEs’ flammability, biotoxicity and enrichment effects was constructed. Thus, 18 dimethyl phthalate (DMP) derivatives and 20 diallyl phthalate (DAP) derivatives were designed based on three-dimensional contour maps. Through evaluation of eco-friendliness and flammability, six eco-friendly PAE derivatives with flame retardancy were screened out. Based on contour maps analysis, it was confirmed that the introduction of large groups and hydrophobic groups was beneficial to the simultaneous improvement of PAEs’ comprehensive effects, and multiple effects. In addition, the group properties were correlated significantly with improved degrees of the comprehensive effects of corresponding PAE derivatives, confirming the feasibility of the comprehensive evaluation method and modified scheme.

Molecular Design of Environment-Friendly PAE Derivatives Based on 3D-QSAR Assisted with a Comprehensive Evaluation Method Combining Toxicity and Estrogen Activities

In this paper, a phthalic acid ester (PAE) three-dimensional quantitative structure-activity relationship (3D-QSAR) model with a double activity (toxicity and estrogenic activities) combination was established using a comprehensive evaluation method, in which the database of the combined activities consisted of 17 and 13 employed in the training sets and test sets, respectively. Ditridecyl phthalate (DTDP) derivatives with low-toxicity and estrogen combined activities were designed with DTDP as the target molecule. Four environmentally friendly DTDP derivatives were screened out by evaluating their environmental friendliness (expressed by persistence, bioaccumulation and migration) and practicability (expressed by insulation). Through the toxicity and estrogen single-activity model validation and contour map analyses, the results showed that the 3D-QSAR model for PAE toxicity and estrogen combined activities was feasible and the weight setting was reasonable. In addition, the mechanism analysis showed that the toxicity and estrogen combined activities of the four DTDP derivatives (2-CH3-DTDP, 2-OCHO-DTDP, 2-CH2COOH-DTDP, 2-CH2OH-DTDP) decreased in turn and were consistent with the single-activity model prediction. Meanwhile, it was speculated that the binding effect of the DTDP derivative molecules and estrogen-related proteins might be related to their hydrophobic interaction.

Environment-friendly PCN derivatives design and environmental behavior simulation based on a multi-activity 3D-QSAR model and molecular dynamics

A multi-activity three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established based on the comprehensive evaluation index (CEI) of polychlorinated naphthalenes (PCNs). The CEI values were calculated using the vector analysis method in combination with the following parameters: biological toxicity (predicted by logEC50), bioconcentration (predicted by logKow), long-distance migration (predicted by logPL), and biodegradation (predicted by total-score). Additionally, sixty-four CN-70 derivatives with lower CEI values were designed, among which three derivatives with reduced CEI values were selected for verification based on an evaluation of their persistent organic pollutant properties and practicability. Finally, an environmental behavior simulation was conducted via molecular dynamics simulation aided by the Taguchi experimental design by considering the degradation characteristics of the three aforementioned CN-70 derivatives as an example. Only two of the selected CN-70 derivatives were observed to be more easily degraded when compared with the CN-70 molecule (ascending range: 11.57 %–13.57 %) in a real-world setting, which was consistent with the biodegradability prediction results (ascending range: 14.94 %–22.49 %) obtained through the molecular docking studies. The multi-activity 3D-QSAR model established in this study overcame the limitations of generating molecular designs based on single-effect models from the source because it focused on the multiple effects of the pollutants.

Highly biodegradable fluoroquinolone derivatives designed using the 3D-QSAR model and biodegradation pathways analysis.

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established based on molecular structures and docking scores (representing the biodegradability); the scores were obtained for 23 fluoroquinolones (FQs) and the oxidoreductase (PDB ID: 1YZP) of Phanerochaete chrysosporium in the aerobic process of municipal wastewater treatment plants. In the Comparative Molecular Field Analysis (CoMFA) model, q2 was 0.516 and r2pred was 0.727, which showed that the model was reliable and robust. The modification information obtained by the contour maps showed that introducing electronegative, bulky or electropositive groups at different active sites could increase the biodegradability of fluoroquinolone derivatives. Using levofloxacin (LEV) as a modified molecule, 35 fluoroquinolone derivatives with higher biodegradability than LEV were designed. After the evaluation of genotoxicity, bioconcentration and photodegradation, Derivative-15, with higher biodegradability (increased by 27.85%), higher genotoxicity, higher photodegradation and lower bioconcentration, was identified as the most environmentally friendly fluoroquinolone derivative. The 2D-QSAR model of FQ biodegradability was established through the quantization parameters, and q+ was identified as the main parameter affecting the biodegradability of FQs through sensitivity analysis. In addition, the docking results of LEV and Derivative-15 with the oxidoreductase in P. chrysosporium showed that the electrostatic field force between Derivative-15 and the amino acid residues promoted the binding of the donor to the receptor protein, thereby increasing the biodegradability of Derivative-15. Additionally, molecular dynamics simulations revealed that the enhancement of the electrostatic field force with Derivative-15 could promote the binding of the ligand to the receptor, which was basically consistent with the conclusion of molecular docking. Finally, the three microbial degradation pathways of LEV and Derivative-15 were also proposed. The total energy barrier value of the pathway with the lowest total energy barrier of biodegradation was reduced by 32.07%, which was basically consistent with the enhancement of biodegradability of Derivative-15.

Studies on Substituted Thienopyridine Carbonitriles as Src Inhibitors Using a Comprehensive In Silico Method

To explore the structural requirements and inhibitory mechanism of Src inhibitors, the comparative molecular field analysis, comparative molecular similarity indices analysis and three-dimensional quantitative structure-activity relationship and molecular docking of 45 substituted thienopyridine carbonitriles as tyrosine kinase pp60src inhibitors was conducted. Three three-dimensional quantitative structure-activity relationship models showed high predictabilities with cross-validated correlation coefficient and predictive correlation coefficient values of 0.793 and 0.887 for comparative molecular field analysis and 0.624 and 0.793 for comparative molecular similarity indices analysis, respectively. Docking results indicated that 4 compounds with high inhibitory activity penetrated into the active pocket of tyrosine kinase pp60src and formed stable hydrogen bonds with the binding pocket of tyrosine kinase pp60src. Leu273, Lys295, Thr338, Asp348, and Ser345 of tyrosine kinase pp60src are important residues. The results could be of great value in designing novel substituted thienopyridine carbonitriles with more potent Src kinase inhibitory activity.

3D-QSAR Analysis and Molecular Docking Studies on 3-Arylcoumarin Derivatives as Potential α- Glucosidase Inhibitors

α-glucosidase inhibitors (AGI) are the structural moieties that are found to be of utmost importance in the fields of pharmacy and which involves delaying the absorption of carbohydrates by blocking of alpha-glucosidase enzyme in the brush border of small intestine and plays an important role in constituting a promising therapeutic class against diabetic disease (Type II). In this study, the three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking models were developed using Fujito-Ban analysis in VALSTAT software and Molegro Virtual Docker 6.0. The theoretical models were generated from 29 3-arylcoumarin inhibitors of α-glucosidase. A robust QSAR model with good prediction in internal and external verification was constructed, where r2 and q2 were 0.821 and 0.646 respectively. The QSAR study suggested that substitution of group at R1 position on 3-arylcoumarin ring with electron withdrawing group favourable for the anti-diabetic activity. Molecular docking studies were performed with the coordinates of the α-glucosidase crystal structure (PDB ID: 3WY2), as the results we found that the ligands would form the hydrogen bond interactions with Asp 202, Arg 400 and Glu 271 of the protein receptor generally. For better α-glucosidase inhibitory activity, dipole seems to give good results. These results of the QSAR analysis and molecular docking provided some useful information for designing new and effective α-glucosidase inhibitors in significance of stability and the binding interaction between ligand the receptor site by considering the validation parameters.

Two-dimensional and Three-dimensional quantitative structure-activity relationship models for the degradation of organophosphate flame retardants during supercritical Water oxidation

Organophosphate flame retardants (OPFRs) have been increasingly utilized as flame retardants in various fields due to the phasing out of polybrominated diphenyl ethers. To achieve a better understanding of the degradation of OPFRs undergoing supercritical water oxidation (SCWO) process, two-dimensional and three-dimensional quantitative structure-activity relationship (2D-QSAR and 3D-QSAR) models were established to investigate the factors influencing the total carbon degradation rates (kTOC). Results of the QSAR models demonstrated reliable results to estimate the kTOC values, but varied in the influencing factors. Two distinct degradation mechanisms were subsequently proposed based on the distribution of LUMO in molecules for the 2D-QSAR model. CoMFA and CoMSIA methods were applied to develop the 3D-QSAR models. Steric fields were observed to influence kTOC values more than electrostatic fields in the CoMFA model with the contribution rates of 87.2% and 12.8%, respectively. In the CoMSIA model, influence on kTOC values varies between different types of fields with the hydrophobic field being the most influential at 62.1%, followed by the steric field at 25.7% and then the electrostatic field at 10.8%. Results from this study generated critical knowledge of influencing factors on OPFRs degradation and yielded theoretical basis for estimating removal behaviors of OPFRs undergoing SCWO process.

Quantitative structure-activity relationship models for bitter-tasting tripeptides based on integrated descriptors

In the present work, three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed in an attempt to predict the key features of bitter-tasting tripeptides. The 3D-QSAR models were carried out by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods and the corresponding statistical correlation coefficients R2cv for the training set are 0.534 and 0.547, respectively, the predicted correlation coefficients R2pred for the test set are found to be 0.7162 and 0.5792, respectively. The information obtained from the QSAR contour maps enables the interpretation of the structure-activity relationship. In addition, molecular docking was also employed to investigate the interaction between bitter-tasting peptides and related receptor hTAS2R1, results indicate that the Lys76, Pro188 and His243 were significant for binding to the peptides, and some essential features were identified to deduce some interesting structure-activity relationships. The present QSAR models along with information contour maps and molecular docking study may be used for designing and predicting novel bitter-tasting peptides.

Synthesis of Thiazolium-Labeled 1,3,4-Oxadiazole Thioethers as Prospective Antimicrobials: In Vitro and in Vivo Bioactivity and Mechanism of Action.

In this study, a type of thiazolium-labeled 1,3,4-oxadiazole thioether bridged by diverse alkyl chain lengths was constructed. The antimicrobial activity of the fabricated thioether toward plant pathogenic bacteria and fungi was then screened. Antibacterial evaluation indicated that title compounds possess specific characteristics that enable them to severely attack three phytopathogens, namely, Xanthomonas oryzae pv. oryzae, Ralstonia solanacearum, and Xanthomonas axonopodis pv. citri with minimal EC50 values of 0.10, 3.27, and 3.50 μg/mL, respectively. Three-dimensional quantitative structure-activity relationship models were established to direct the following excogitation for exploring higher active drugs. The in vivo study against plant bacterial diseases further identified the prospective application of title compounds as alternative antibacterial agents. The proteomic technique, scanning electron microscopy patterns, and fluorescence spectrometry were exploited to investigate the antibacterial mechanism. Additionally, some target compounds performed superior inhibitory actions against three tested fungal strains. In view of their simple molecular architecture and highly efficient bioactivity, these substrates could be further explored as promising surrogates for fighting against plant microbial infections.

Virtual identification of novel peroxisome proliferator-activated receptor (PPAR) α/δ dual antagonist by 3D-QSAR, molecule docking, and molecule dynamics simulation

The therapeutic potential of PPARs antagonists extends beyond diabetes. PPARs antagonists represent a new drug class that holds promise as a broadly applicable therapeutic approach for cancer treatment. Thus, there is a strong need to develop a rational design strategy for creating PPARs antagonists. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) models of PPARα receptor (CoMFA-1, q 2 = 0.636, r 2 = 0.953; CoMSIA-1, q 2 = 0.779, r 2 = 0.999) and PPARδ receptor (CoMFA-2, q 2 = 0.624, r 2 = 0.906; CoMSIA-2, q 2 = 0.627, r 2 = 0.959) were successfully constructed using 35 triazolone ring derivatives. Contour map analysis revealed that the electrostatic and hydrophobic fields played vital roles in the bioactivity of dual antagonists. Molecular docking studies suggested that the hydrogen bonding, electrostatic and hydrophobic interactions all influenced the binding of receptor-ligand complex. Based on the information obtained above, we designed a series of compounds. The docking results were mutually validated with 3D-QSAR results. Three-dimensional-QSAR and absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions indicated that 19 newly designed compounds possessed excellent biological activity and physicochemical properties. In summary, this research could provide theoretical guidance for the structural optimization of novel PPARα and δ dual antagonists. Communicated by Ramaswamy H. Sarma