Development Of Quantitative Structure-activity Relationship Models Research Articles

The mixture toxicity of heavy metals on Photobacterium phosphoreum and its modeling by ion characteristics-based QSAR.

Organisms are frequently exposed to mixtures of heavy metals because of their persistence in the environment. The mixture toxicity of heavy metals should therefore be evaluated to perform a rational environmental risk assessment for organisms. In this study, we determined the inhibition toxicity of five heavy metals (Cu2+, Co2+, Zn2+, Fe3+ and Cr3+) and their binary mixtures to Photobacterium phosphoreum (P. phosphoreum). We obtained the following results: (1) the order of individual toxicity was Zn2+>Cu2+>Co2+>Cr3+>Fe3+, and (2) different combined effects (additive, synergistic and antagonistic) were observed in the binary mixtures of heavy metals, with toxicity unit (TU) values ranging from 0.15 to 3.50. To predict the mixture toxicity of heavy metals, we derived the ion characteristic parameters of heavy metal mixtures and explored the ion-characteristic-based quantitative structure–activity relationship (QSAR) model (R2 = 0.750, Q2 = 0.649). The developed QSAR model indicated that the mixture toxicity of heavy metals is related to the change in ionization potential ((ΔIP)mix), the first hydrolysis constant (log(KOH)mix) and the formation constant value ().

Prediction of Terpenoid Toxicity Based on a Quantitative Structure-Activity Relationship Model.

Terpenoids, including monoterpenoids (C10), norisoprenoids (C13), and sesquiterpenoids (C15), constitute a large group of plant-derived naturally occurring secondary metabolites with highly diverse chemical structures. A quantitative structure–activity relationship (QSAR) model to predict terpenoid toxicity and to evaluate the influence of their chemical structures was developed in this study by assessing in real time the toxicity of 27 terpenoid standards using the Gram-negative bioluminescent Vibrio fischeri. Under the test conditions, at a concentration of 1 µM, the terpenoids showed a toxicity level lower than 5%, with the exception of geraniol, citral, (S)-citronellal, geranic acid, (±)-α-terpinyl acetate, and geranyl acetone. Moreover, the standards tested displayed a toxicity level higher than 30% at concentrations of 50–100 µM, with the exception of (+)-valencene, eucalyptol, (+)-borneol, guaiazulene, β-caryophellene, and linalool oxide. Regarding the functional group, terpenoid toxicity was observed in the following order: alcohol > aldehyde ~ ketone > ester > hydrocarbons. The CODESSA software was employed to develop QSAR models based on the correlation of terpenoid toxicity and a pool of descriptors related to each chemical structure. The QSAR models, based on t-test values, showed that terpenoid toxicity was mainly attributed to geometric (e.g., asphericity) and electronic (e.g., maximum partial charge for a carbon (C) atom (Zefirov’s partial charge (PC)) descriptors. Statistically, the most significant overall correlation was the four-parameter equation with a training coefficient and test coefficient correlation higher than 0.810 and 0.535, respectively, and a square coefficient of cross-validation (Q2) higher than 0.689. According to the obtained data, the QSAR models are suitable and rapid tools to predict terpenoid toxicity in a diversity of food products.

Predicting acute contact toxicity of organic binary mixtures in honey bees (A. mellifera) through innovative QSAR models

Pollinators such as honey bees are of considerable importance, because of the crucial pollination services they provide for food crops and wild plants. Since bees are exposed to a wide range of multiple chemicals “mixtures” both of anthropogenic (e.g. plant protection products) and natural origin (e.g. plant toxins), understanding their combined toxicity is critical. Although honey bees are employed worldwide as surrogate species for Apis and non-Apis bees in toxicity tests, it is practically unfeasible to perform in vivo tests for all mixtures of chemicals. Therefore, Quantitative Structure-Activity Relationships (QSAR) models can be developed using available data and can provide useful tools to predict such combined toxicity. Here, three different QSAR models within the CORAL software have been calibrated and validated for honey bees (A. mellifera) to predict the acute contact mixtures potency (LD50-mix), in two regression based-models, and the nature of combined toxicity (synergism / non-synergism) in a classification-based model. Experimental data on binary mixtures (n = 123) (LD50-mix) including dose response data (n = 97) and corresponding Toxic Unit values were retrieved from EFSA databases. The models were built using the principle of extraction of attributes from SMILES (or quasi-SMILES) while calculating so-called correlation weights for these attributes using Monte Carlo techniques. The two regression models were validated for their reliability and robustness (R2 = 0.89, CCC = 0.92, Q2 = 0.81; R2 = 0.87, CCC = 0.89, Q2 = 0.75). The classification model was validated using sensitivity (=0.86), specificity (=1), accuracy (=0.96), and Matthews correlation coefficient (MCC = 0.90) as qualitative statistical validation parameters. Results indicate that these QSAR models successfully predict acute contact toxicity of binary mixtures in honey bees and can support prioritisation of multiple chemicals of concerns. Data gaps and further development of QSAR models for honey bees are highlighted particularly for chronic and sub-lethal effects.

QSAR and docking studies on Triazole Benzene Sulfonamides with human Carbonic anhydrase IX inhibitory activity

AbstractCancer is the second leading cause of death worldwide, and breast cancer accounts for 2.09 million cases in the year 2018. Hypoxia‐related human carbonic anhydrase IX enzyme was found to play a key role in metastasis also. In this view, quantitative structure activity relationship (QSAR) studies were carried out by QSARINS on triazole benzene sulfonamide derivatives for carbonic anhydrase IX inhibitory activity targeting breast cancer. A new scope to explore 3D‐MoRSE descriptors in carbonic anhydrase inhibition has been initiated by this study. The best model 3 generated includes five variables MoRSEV22, MoRSEC17, MoRSEV1, MoRSEC4, and MoRSEE2 with statistical values R2 = 0.7852, CCCtr = 0.8797, Q2LOO = 0.7237, Q2LMO = 0.7071, CCCcv = 0.8472, R2ext = 0.7894, and CCCext = 0.8784. The developed QSAR model suggests that the atomic volume, atomic charges, and Sanderson's electronegativity play key roles and were extremely helpful in designing and optimizing the lead. Molecular docking studies were performed using Autodock v 4.2.6 and the residues of active site region involving both hydrophilic and hydrophobic parts interacted with best predicted active compounds 1d, 3e, 6f and 9f. The study leads to the development of new inhibitors targeting breast cancer.

A review of recent advances towards the development of QSAR models for toxicity assessment of ionic liquids

•Ionic liquids (ILs) are considered as an alternative to traditional organic solvents due to their unique physical and chemical properties. On the one hand, they have promising solvating characteristics, on the other hand, they are considered as environmentally friendly “green” solvents. Recent studies of ILs toxicity however questioned the safety of ILs.•Assessment of the toxicity of ILs based on laboratory testing is time-consuming and requires significant resources. Complementing this task by applying computational methods is an option for filling data gaps and allows predicting the toxicity of ILs that lack experimental data. Development and application of quantitative structure–activity relationships (QSARs) for innovative design of safe-by-design ILs became recently a research priority. In this review, we summarize the current knowledge on development of in silico models in predicting and classifying the hazards of ILs. In addition, we discuss biodegradability of ILs and assessment of mechanisms of toxicity of ILs based on the reported models.

Prediction on the mutagenicity of nitroaromatic compounds using quantum chemistry descriptors based QSAR and machine learning derived classification methods

Nitroaromatic compounds (NACs) are an important type of environmental organic pollutants. However, it is lack of sufficient information relating to their potential adverse effects on human health and the environment due to the limited resources. Thus, using in silico technologies to assess their potential hazardous effects is urgent and promising. In this study, quantitative structure activity relationship (QSAR) and classification models were constructed using a set of NACs based on their mutagenicity against Salmonella typhimurium TA100 strain. For QSAR studies, DRAGON descriptors together with quantum chemistry descriptors were calculated for characterizing the detailed molecular information. Based on genetic algorithm (GA) and multiple linear regression (MLR) analyses, we screened descriptors and developed QSAR models. For classification studies, seven machine learning methods along with six molecular fingerprints were applied to develop qualitative classification models. The goodness of fitting, reliability, robustness and predictive performance of all developed models were measured by rigorous statistical validation criteria, then the best QSAR and classification models were chosen. Moreover, the QSAR models with quantum chemistry descriptors were compared to that without quantum chemistry descriptors and previously reported models. Notably, we also obtained some specific molecular properties or privileged substructures responsible for the high mutagenicity of NACs. Overall, the developed QSAR and classification models can be utilized as potential tools for rapidly predicting the mutagenicity of new or untested NACs for environmental hazard assessment and regulatory purposes, and may provide insights into the in vivo toxicity mechanisms of NACs and related compounds.

QSAR and molecular docking studies of lethal factor protease inhibitors against Bacillus anthracis

ABSTRACTBacillus anthracis is considered as a biological warfare agent because it is the causative agent of the serious infectious anthrax disease. Delay in treatment leads to lethal factor-mediated toxaemia which is very critical due to lack of therapeutic options. Consequently, attempts have been made to discover potent lethal factor (LF) protease inhibitors such as small-molecule synthetic 2-thio-1,3-thiazolidine-4-one (rhodanine) compounds. But computed descriptor-based quantitative structure–activity relationship (QSAR) and drug design studies on such aspect are poorly represented. Therefore, an attempt was made for developing QSAR models using structural descriptors for 1,3-thiazolidine-4-one compounds. The models were developed on a series of 49 LF protease inhibitors using the combination of constitutional, functional group, atom-centred fragment and molecular property descriptors. The best QSAR model included four variables, namely, C-040, nR05, GVWAI-80 and ALOGP that correlated well with the anti-LF protease activity with a good correlation coefficient (r = 0.870) of good statistical significance (F4, 29 = 14.09 (α = 0.001) F4, 29 = 6.19). This model was also validated and explained 58.1% of variances of the Bacillus anthracis inhibitory activities of the studied compounds with r2pred = 0.710 which denotes external predictability. Finally, molecular docking was carried out to predict the mode of binding of some highly active congeneric compounds. It was shown that VAL 1403 is an important residue for phenyl ring. TYR 1456 and HIS 1418 are responsible for interaction with the rhodanine nucleus. Therefore, these residues are considered responsible for the inhibition of LF protease anthrax and can predict significant dimension of essential structural features of these inhibitors to evaluate, screen and help priorities of the synthesis of the candidates against anthrax bioterrorism.

New Workflow for QSAR Model Development from Small Data Sets: Small Dataset Curator and Small Dataset Modeler. Integration of Data Curation, Exhaustive Double Cross-Validation, and a Set of Optimal Model Selection Techniques.

Quantitative structure-activity relationship (QSAR) modeling is a well-known in silico technique with extensive applications in several major fields such as drug design, predictive toxicology, materials science, food science, etc. Handling small-sized datasets due to the lack of experimental data for specialized end points is a crucial task for the QSAR researcher. In the present study, we propose an integrated workflow/scheme capable of dealing with small dataset modeling that integrates dataset curation, "exhaustive" double cross-validation and a set of optimal model selection techniques including consensus predictions. We have developed two software tools, namely, Small Dataset Curator, version 1.0.0, and Small Dataset Modeler, version 1.0.0, to effortlessly execute the proposed workflow. These tools are freely available for download from https://dtclab.webs.com/software-tools . We have performed case studies employing seven diverse datasets to demonstrate the performance of the proposed scheme (including data curation) for small dataset QSAR modeling. The case studies also confirm the usability and stability of the developed software tools.

Nucleobase sequence based building up of reliable QSAR models with the index of ideality correlation using Monte Carlo method

This study describes in silico designing of aptamers against the influenza virus using Monte Carlo method. Aptamers are short, single-stranded oligonucleotides and these bind to an ample range of biologically important proteins which are related to many disease conditions. The affinities and specificities of aptamers are comparable to antibodies. In the medicinal chemistry, quantitative structure-activity relationship (QSAR) is an important skill which is used for drug design and development. To study the inhibitory activity of aptamers, we have developed QSAR models based on Monte Carlo method. The nucleobase sequence descriptors Bk, BBk and BBBk are used to generate the QSAR models. A number of statistical benchmarks together with index of ideality of correlation (IIC) is considered to validate the build QSAR models. Data set of 98 aptamers is divided into four random splits. The statistical criteria R2 = 0.8711 and CCC = 0.9207 of the validation set of split 3 are best, so the build QSAR model of split 3 is the paramount model. The aptamer fragment responsible for the promotors of endpoint increase and decrease are also determined. These fragments are applied to design new nine aptamers from the lead aptamer APT01.Communicated by Ramaswamy H. Sarma

In silico design of diacylglycerol acyltransferase-1 (DGAT1) inhibitors based on SMILES descriptors using Monte-Carlo method

ABSTRACTDiabetes, obesity and other diseases related to metabolism are worldwide health problems. These syndromes can be well treated when a particular enzyme-based therapy is developed. Diacylglycerol acyltransferase (DGAT; EC 2.3.1.20) is a microsomal enzyme which is responsible for the synthesis of triglycerides from 1,2-diacylglycerol by catalyzing the acyl-CoA-dependent acylation. The obesity and type-II diabetes can be checked by the inhibition of DGAT1 enzyme. Quantitative structure–activity relationship (QSAR) modelling is an essential technique in drug design and development. To study the aspect of DGAT1 inhibitors, Monte-Carlo method-based QSAR was developed for 197 DGAT1 inhibitors. QSAR models were derived by using the optimal descriptor based on SMILES notation. Different statistical parameters including the novel index of ideality of correlation were applied to validate the generated QSAR models. Four random splits were prepared from the data set. The statistical criteria r2 = 0.8129, CCC = 0.8979 and Q2 = 0.7962 of the validation set of split 1 were the best; therefore, the developed QSAR model of split 1 was decided to be the leading model. The molecular fragments, which were promoter of endpoint increase or decrease were also determined. Thirteen new DGAT1 inhibitors were designed from the lead compound DGAT011.

UV direct photolysis of halogenated disinfection byproducts: Experimental study and QSAR modeling

UV direct photolysis has been used as a promising process to remove halogenated disinfection byproducts (DBPs) generated in water. In this study, experimental studies and modeling approaches were applied to investigate the UV direct photolysis rate constants for 40 kinds of halogenated DBPs. The fluence-based pseudo-first-order rate constants for the removal of halogenated DBPs under UV photolysis spanned more than 2 orders of magnitude, with a range of (0.23–29.84) × 10−4 cm2 mJ−1. DBPs with higher number of halogenated substituents featured higher photolysis rate constants. The degradation efficiencies of DBPs were also affected by the species of halogen substituents, which followed the trend of iodo- > bromo- > chloro- DBPs. A quantitative structure-activity relationship (QSAR) model was established on the basis of the observed degradation rate constant values, which contained a quantum-chemical descriptor (ELUMO–EHOMO) and a molecular descriptor (Eta_C). The calculated parameters of the developed model indicated its good robustness and high reliability. The developed QSAR model can predict the degradation rate constants for DBPs within factors of 1/3 to 3. The model was validated using application domain and visualized in a Williams plot. The selected descriptors for QSAR model can explain the reaction mechanism for UV direct photolysis.

Models for skin and brain penetration of major components from essential oils used in aromatherapy for dementia patients

Aromatherapy with essential oils (EOs) has been linked to improvement of cognitive function in patients with dementia. In order to act systemically, active EO components must be absorbed through the skin, enter the systemic circulation, and cross the blood brain barrier (BBB). Thus, the aim of this work was to develop quantitative structure activity relationships (QSARs), to predict skin and blood barrier penetrative abilities of 119 terpenoids from EOs used in aromatherapy. The first model was based on experimentally measured skin permeability for 162 molecules, and the second model on BBB permeability for 138 molecules. Each molecule was encoded with 63 calculated molecular descriptors and an artificial neural network was used to correlate molecular descriptors to permeabilities. Developed QSAR models confirm that EOs components penetrate through the skin and across the BBB. Some well-known descriptors, such as log P (lipophilicity), molecular size and shape, dominated the QSAR model for BBB permeability. Compounds with the highest predicted BBB penetration were hydrocarbon terpenes with the smallest molecular size and highest lipophilicity. Thus, molecular size is a limiting factor for penetration. Compounds with the highest skin permeability have slightly higher molecular size, high lipophilicity and low polarity. Our work shows that a major disadvantage of novel multitarget compounds developed for the treatment of Alzheimer’s disease is the size of molecules, which cause problems in their delivery to the brain. Therefore, there is a need for smaller compounds, which possess more desirable physicochemical properties and pharmacokinetics, in addition to targeted biological effects.Communicated by Ramaswamy H. Sarma

Development of Predictive Antioxidant Models for 1,3,4-Oxadiazoles by Quantitative Structure Activity Relationship

The free radical scavenging properties of 1,3,4-oxadiazoles have been explored by the application of quantitative structure activity relationship (QSAR) studies. The entire data set of the oxadiazole derivatives were minimized and subsequently optimized at the density functional theory (DFT) level in combination with the Becke's three-parameter Lee-Yang-Parr hybrid functional (B3LYP) hybrid functional and 6-311G* basis set. Kennard Stone algorithm was employed in data division into training and test sets. The training set were employed in QSAR model development by genetic function algorithm (GFA), while the test set were used to validate the developed models. The applicability domain of the developed model was accessed by the leverage approach. The varation inflation factor, degree of contribution and mean effect of each descriptor were calculated. Quantum chemical and molecular descriptors were generated for each molecule in the data set. Five predictive models that met all the requirements for acceptability with good validation results were developed. The best of the five models gave the following validation results: , , and c , rmsep . The QSAR analysis revealed that the sum of e-state descriptors of strength for potential hydrogen bonds of path length 9 (SHBint9) and topological radius (topoRadius) are the most crucial descriptors that influence the free radical scavenging activities of 1,3,4-oxadiazole derivatives.

In silico prediction of cutaneous penetration rate of some chemicals from their molecular structural descriptors

The cutaneous penetration rate of some hormones and organic solvents to the stratum corneum was modeled and estimated by using interpretable molecular descriptors. To develop quantitative structure–activity relationship (QSAR) models, the methods of multiple linear regression and artificial neural network were used. The results of this study indicated the ability of the developed QSAR models in the prediction of the dermal penetration rate of various chemicals from their calculated molecular descriptors.

Ecotoxicological QSAR modeling of organic compounds against fish: Application of fragment based descriptors in feature analysis

Organic compounds (OCs) constitute an enormously large class of highly persistent and toxic chemicals widely used for various purposes throughout the world. Their increased detection in water bodies, mainly sewage treatment plants via industrial discharge, has rendered them to become a cause for ecological concern. The limited availability of experimental toxicological data has necessitated development of models that can help us identify the most hazardous and potentially toxic compounds thus prioritizing the experiments on the selected chemicals. Computational tools such as quantitative structure-activity relationship (QSAR) can be used to predict the missing data and classify the chemicals based on their acute predicted responses for existing as well as not yet synthesized chemicals. In the current study, novel, externally validated, highly robust local QSAR models for different chemical classes and moderately robust global QSAR models were developed using partial least squares (PLS) regression technique using a large dataset of 1121 OCs for the fish mortality endpoint. For feature selection, genetic algorithm along with stepwise regression was used while model validation was performed using various stringent validation criteria following the strict rules of OECD guidelines of QSAR validation. The variables included in the models were obtained from simplex representation of molecular structures (SiRMS) (Version 4.1.2.270), Dragon (Version 7.0) and PaDEL-descriptor software (Version 2.20). The final developed models were robust, externally predictive and characterized by a large chemical as well as biological domain. The predictive efficiency of the developed models was then compared with the ECOSAR tool in order to justify the applicability of the developed models in ecotoxicological predictions for organic chemicals. Better predictive efficiency of the developed QSAR models compared to the ECOSAR derived predictions signifies their applicability in early risk assessment of known as well as untested chemicals in order to design safer alternatives to the environment.

Image-based QSAR Model for the Prediction of P-gp Inhibitory Activity of Epigallocatechin and Gallocatechin Derivatives.

Permeability glycoprotein (P-gp) is one of the cell membrane proteins that can push some drugs out of the cell causing drug tolerance and its inhibition can prevent drug resistance. In this study, we used image-based Quantitative Structure-Activity Relationship (QSAR) models to predict the P-gp inhibitory activity of epigallocatechin and gallocatechin derivatives. The 2D-chemical structures and their P-gp inhibitory activity were taken from literature. The pixels of images and their Principal Components (PCs) were calculated using MATLAB software. Principle Component Regression (PCR), Artificial Neural Network (ANN) and Support Vector Machine (SVM) approaches were used to develop QSAR models. Statistical parameters included the leave one out cross-validated correlation coefficient (q2) for internal validation of the models and R2 of test set, Root Mean Square Error (RMSE) and Concordance Correlation Coefficient (CCC) were applied for external validation. Six PCs from image analysis method were selected by stepwise regression for developing linear and non-linear models. Non-linear models i.e. ANN (with the R2 of 0.80 for test set) were chosen as the best for the established QSAR models. According to the result of the external validation, ANN model based on image analysis method can predict the P-gp inhibitory activity of epigallocatechin and gallocatechin derivatives better than the PCR and SVM models.

Development of quantitative structure-activity relationship models to predict potential nephrotoxic ingredients in traditional Chinese medicines

The broad use of traditional Chinese medicines (TCMs) and the accompanied incidences of kidney injury have attracted considerable interest in investigating the responsible toxic ingredients. It is challenging to evaluate toxicity of TCMs since they contain complex mixtures of phytochemicals. Quantitative structure-activity relationship (QSAR) is an efficient tool to predict toxicity and QSAR study on TCMs-induced nephrotoxicity remains lacked. We developed QSAR models using three datasets of 609 compounds: natural products, drugs, and mixed (contained both kinds of data) datasets. Each dataset was used for modelling by utilizing artificial neural networks (ANN) and support vector machines (SVM) algorithms separately. Both internal and external validations were performed on each model. Six QSAR models were developed and yielded reliable performance in the internal validation. For external validation, 30 ingredients in the TCMs were predicted well by the natural product models (accuracy: ANN 96.7%, SVM 93.3%). The mixed models (accuracy: ANN 76.7%, SVM 66.7%) showed a better performance than the drug models (accuracy: ANN 50%, SVM 53.3%). Particularly, natural product models produced the most reliable results. It has the application not only on screening the nephrotoxic ingredients in TCMs, but it is also helpful at prioritizing the subsequent toxicity testing of natural products.

Construction of a Quantitative Structure Activity Relationship (QSAR) Model to Predict the Absorption of Cephalosporins in Zebrafish for Toxicity Study

Cephalosporins are beta-lactam antibiotics that are widely used in China. Five generations of cephalosporins have been introduced in clinical practice to date; moreover, some new candidates are also undergoing clinical evaluations. To improve the success rates of new drug development, we need to have a comprehensive understanding about the relationship between the structure of cephalosporins and the toxicity that it induces at an early stage. In the cephalosporins toxicity study using zebrafish, the drug absorption is a key point. In this study, we determined the absorption of cephalosporins in zebrafish during toxicity test. The internal concentrations of 19 cephalosporins in zebrafish were determined using a developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Furthermore, a quantitative structure-activity relationship (QSAR) model was established by multilinear regression; moreover, it was used to predict the absorption of cephalosporins in zebrafish. During leave-one-out cross-validation, a satisfactory performance was obtained with a predictive ability (q2) of 0.839. The prediction ability of the model was further confirmed when the predictive ability (q2) was 0.859 in external prediction. The best QSAR model, which was based on five molecular descriptors, exhibited a promising predictive performance and robustness. In experiments involving drug toxicity, the developed QSAR model was used to estimate internal concentrations of cephalosporins. Thus, the toxicity results were correlated with the internal concentration of the drug within the larvae. The developed model served as a new powerful tool in zebrafish toxicity tests.

In silico studies and the design of novel agents for the treatment of systemic tuberculosis

Tuberculosis (TB) is an ancient infectious disease, which re-emerged with the appearance of multidrug-resistant strains and acquired immune deficiency syndrome. Enoyl-acyl-carrier protein reductase (InhA) has emerged as a promising target for the development of anti-tuberculosis therapeutics. This study aims to develop quantitative structure-activity relationship (QSAR) models for a series of arylcarboxamides as InhA inhibitors. The QSAR models were calculated on the basis of optimal molecular descriptors based on the simplified molecular-input line-entry system (SMILES) notation with the Monte Carlo method as a model developer. The molecular docking study was used for the final assessment of the developed QSAR model and designed novel inhibitors. Methods used for the validation indicated that the predictability of the developed model was good. Structural indicators defined as molecular fragments responsible for increases and decreases of the studied activity were defined. The computer-aided design of new compounds as potential InhA inhibitors was presented. The Monte Carlo optimization was capable of being an efficient in silico tool for developing a model of good statistical quality. The predictive potential of the applied approach was tested and the robustness of the model was proven using different methods. The results obtained from molecular docking studies were in excellent correlation with the results from QSAR studies. This study can be useful in the search for novel anti-tuberculosis therapeutics based on InhA inhibition.Communicated by Ramaswamy H. Sarma

Comprehensive 3D-QSAR Model Predicts Binding Affinity of Structurally Diverse Sigma 1 Receptor Ligands.

The Sigma 1 Receptor (S1R) has attracted intense interest as a pharmaceutical target for various therapeutic indications, including the treatment of neuropathic pain and the potentiation of opioid analgesia. Efforts by drug developers to rationally design S1R antagonists have been spurred recently by the 2016 publication of the high-resolution X-ray crystal structure of the ligand-bound human S1R. Until now, however, the absence in the published literature of a single, large-scale, and comprehensive quantitative structure-activity relationship (QSAR) model that encompasses a structurally diverse collection of S1R ligands has impaired rapid progress. To our best knowledge, the present study represents the first report of a statistically robust and highly predictive 3D-QSAR model (R2 = 0.92, Q2 = 0.62, Rpred2 = 0.81) based on the X-ray crystal structure of human S1R and constructed from a pooled compilation of 180 S1R antagonists that encompass five structurally diverse chemical families investigated using identical experimental protocols. Best practices, as recommended by the Organization for Economic Cooperation and Development (OECD: http://www.oecd.org/ ), were adopted for pooling data from disparate sources and for QSAR model development and both internal and external model validation. The practical utility of the final 3D-QSAR model was tested by virtual screening of the DrugBank database of FDA approved drugs supplemented by eight reported S1R antagonists. Among the top-ranked 40 DrugBank hits, four approved drugs which were previously unknown as S1R antagonists were tested using in vitro radiolabeled human S1R binding assays. Of these, two drugs (diphenhydramine and phenyltoloxamine) exhibited potent S1R binding affinity with Ki = 58 nM and 160 nM, respectively. As diphenhydramine is approved as an antiallergic, and phenyltoloxamine as an analgesic and sedative, each of these compounds represents a viable starting point for a drug discovery campaign aimed at the development of novel S1R antagonists for a wide range of therapeutic indications.