Monastrol suppresses invasion and metastasis in human colorectal cancer cells by targeting fascin independent of kinesin-Eg5 pathway.

Rearrangement of the actin cytoskeleton is a prerequisite for carcinoma cells to develop cellular protrusions, which are required for migration, invasion, and metastasis. Fascin is a key protein involved in actin bundling and is expressed in aggressive and invasive carcinomas. Additionally, fascin appears to be involved in tubulin-binding and microtubule rearrangement. Pharmacophoric-based in silico screening was performed to identify compounds with better fascin inhibitory properties than migrastatin, a gold-standard fascin inhibitor. We hypothesized that monastrol displays anti-migratory and anti-invasive properties via fascin blocking in colorectal cancer cell lines. Biophysical (thermofluor and ligand titration followed by fluorescence spectroscopy), biochemical (NMR), and cellular assays (MTT, invasion of human tissue), as well as animal model studies (zebrafish invasion) were performed to characterize the inhibitory effect of monastrol on fascin activity. In silico analysis revealed that monastrol is a potential fascin-binding compound. Biophysical and biochemical assays demonstrated that monastrol binds to fascin and interferes with its actin-bundling activity. Cell culture studies, including a 3D human myoma disc model, showed that monastrol inhibited fascin-driven cytoplasmic protrusions as well as invasion. In silico, confocal microscopy, and immunoprecipitation assays demonstrated that monastrol disrupted fascin-tubulin interactions. These anti-invasive effects were confirmed in vivo. In silico confocal microscopy and immunoprecipitation assays were carried out to test whether monastrol disrupted the fascin-tubulin interaction. This study reports, for the first time, the in vitro and in vivo anti-invasive properties of monastrol in colorectal tumor cells. The number and types of interactions suggest potential binding of monastrol across actin and tubulin sites on fascin, which could be valuable for the development of antitumor therapies.

2D finger-printing and molecular docking studies identified potent mosquito repellents targeting odorant binding protein 1.

Personal protection measures against the mosquitoes like the use of repellents constitute valuable tools in the effort to prevent the transmission of vector-borne diseases. Therefore, the discovery of novel repellent molecules which will be effective at lower concentrations and provide a longer duration of protection remains an urgent need. Mosquito Odorant-Binding Proteins (OBPs) involved in the initial steps of the olfactory signal transduction cascade have been recognized not only as passive carriers of odors and pheromones but also as the first molecular filter to discriminate semiochemicals, hence serving as molecular targets for the design of novel pest control agents. Among the three-dimensional structures of mosquito OBPs solved in the last decades, the OBP1 complexes with known repellents have been widely used as reference structures in docking analysis and molecular dynamics simulation studies for the structure-based discovery of new molecules with repellent activity. Herein, ten compounds known to be active against mosquitoes and/or displaying a binding affinity for Anopheles gambiae AgamOBP1 were used as queries in an in silico screening of over 96 million chemical samples in order to detect molecules with structural similarity. Further filtering of the acquired hits on the basis of toxicity, vapor pressure, and commercial availability resulted in 120 unique molecules that were subjected to molecular docking studies against OBP1. For seventeen potential OBP1-binders, the free energy of binding (FEB) and mode of interaction with the protein were further estimated by molecular docking simulations leading to the selection of eight molecules exhibiting the highest similarity with their parental compounds and favorable energy values. The in vitro determination of their binding affinity to AgamOBP1 and the evaluation of their repellent activity against female Aedes albopictus mosquitoes revealed that our combined ligand similarity screening and OBP1 structure-based molecular docking successfully detected three molecules with enhanced repellent properties. A novel DEET-like repellent with lower volatility (8.55 × 10-4 mmHg) but a higher binding affinity for OBP1 than DEET (1.35 × 10-3 mmHg). A highly active repellent molecule that is predicted to bind to the secondary Icaridin (sIC)-binding site of OBP1 with higher affinity than to the DEET-site and, therefore, represents a new scaffold to be exploited for the discovery of binders targeting multiple OBP sites. Finally, a third potent repellent exhibiting a high degree of volatility was found to be a strong DEET-site binder of OBP1 that could be used in slow-release formulations.

Fishing the Targets of Bioactive Compounds from Psidium guajava L. Leaves in the Context of Diabetes.

Psidium guajava L. (guava) leaves have demonstrated their in vitro and in vivo effect against diabetes mellitus (DM). However, there is a lack of literature concerning the effect of the individual phenolic compounds present in the leaves in DM disease. The aim of the present work was to identify the individual compounds in Spanish guava leaves and their potential contribution to the observed anti-diabetic effect. Seventy-three phenolic compounds were identified from an 80% ethanol extract of guava leaves by high performance liquid chromatography coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry. The potential anti-diabetic activity of each compound was evaluated with the DIA-DB web server that uses a docking and molecular shape similarity approach. The DIA-DB web server revealed that aldose reductase was the target protein with heterogeneous affinity for compounds naringenin, avicularin, guaijaverin, quercetin, ellagic acid, morin, catechin and guavinoside C. Naringenin exhibited the highest number of interactions with target proteins dipeptidyl peptidase-4, hydroxysteroid 11-beta dehydrogenase 1, aldose reductase and peroxisome proliferator-activated receptor. Compounds catechin, quercetin and naringenin displayed similarities with the known antidiabetic drug tolrestat. In conclusion, the computational workflow showed that guava leaves contain several compounds acting in the DM mechanism by interacting with specific DM protein targets.

Carvacrol and HP-ß-Cyclodextrin Complexes: Extensive Characterization and Potential Cytotoxic Effect in Human Colorectal Carcinoma Cells.

The aim of this study was to obtain solid carvacrol-cyclodextrin (CD) complexes for use in the pharmaceutical industry. To this end, the complexation of carvacrol at different pH values was studied in detail, to determine the type of CD and the reaction environment that supported the highest amount of encapsulated carvacrol. Evidence of the capability of hydroxypropyl-ß-cyclodextrins (HP-ß-CD) to form inclusion complexes with carvacrol (KC = 5042 ± 176 L mol-1) and more high complexation efficiency (2.824) was demonstrated for HP-ß-CDs using two different energy sources, ultrasound (US) (KC = 8129 ± 194 L mol-1 24 h) and microwave irradiation (MWI) (KC = 6909 ± 161 L mol-1), followed by spraying the resulting solution in a spray dryer. To confirm complex formation, the complexes were characterized using various instrumental methods to corroborate the carvacrol incorporation into the hydrophobic cavity of HP-ß-CD. The obtained carvacrol solid complexes were analyzed by 1H nuclear magnetic resonance (1H-NMR) and 2D nuclear magnetic resonance (ROSEY), differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and Fourier transform infrared spectroscopy (FTIR) characterization. The structures of the resulting complexes were also characterized by molecular modeling. Furthermore, 1 mM HP-ß-CD-carvacrol complex has been shown to reduce cell proliferation in HCT-116 colorectal cancer cells by 43%, much more than in a healthy lung fibroblast MRC-5 cell line (11%).

Identification of Kukoamine A, Zeaxanthin, and Clexane as New Furin Inhibitors.

The endogenous protease furin is a key protein in many different diseases, such as cancer and infections. For this reason, a wide range of studies has focused on targeting furin from a therapeutic point of view. Our main objective consisted of identifying new compounds that could enlarge the furin inhibitor arsenal; secondarily, we assayed their adjuvant effect in combination with a known furin inhibitor, CMK, which avoids the SARS-CoV-2 S protein cleavage by means of that inhibition. Virtual screening was carried out to identify potential furin inhibitors. The inhibition of physiological and purified recombinant furin by screening selected compounds, Clexane, and these drugs in combination with CMK was assayed in fluorogenic tests by using a specific furin substrate. The effects of the selected inhibitors from virtual screening on cell viability (293T HEK cell line) were assayed by means of flow cytometry. Through virtual screening, Zeaxanthin and Kukoamine A were selected as the main potential furin inhibitors. In fluorogenic assays, these two compounds and Clexane inhibited both physiological and recombinant furin in a dose-dependent way. In addition, these compounds increased physiological furin inhibition by CMK, showing an adjuvant effect. In conclusion, we identified Kukoamine A, Zeaxanthin, and Clexane as new furin inhibitors. In addition, these drugs were able to increase furin inhibition by CMK, so they could also increase its efficiency when avoiding S protein proteolysis, which is essential for SARS-CoV-2 cell infection.

Combined Structure and Ligand-Based Design of Selective Acetylcholinesterase Inhibitors.

Acetylcholinesterase is a prime target for therapeutic intervention in Alzheimer's disease. Acetylcholinesterase inhibitors (AChEIs) are used to improve cognitive abilities, playing therefore an important role in disease management. Drug repurposing screening has been performed on a corporate chemical library containing 11 353 compounds using a target fishing approach comprising three-dimensional (3D) shape similarity and pharmacophore modeling against an approved drug database, Drugbank. This initial screening identified 108 hits. Among them, eight molecules showed structural similarity to the known AChEI drug, pyridostigmine. Further structure-based screening using a pharmacophore-guided rescoring method identifies one more potential hit. Experimental evaluations of the identified hits sieve out a highly selective AChEI scaffold. Further lead optimization using a substructure search approach identifies 24 new potential hits. Three of the 24 compounds (compounds 10b, 10h, and 10i) based on a 6-(2-(pyrrolidin-1-yl)pyrimidin-4-yl)-thiazolo[3,2-a]pyrimidine scaffold showed highly promising AChE inhibition ability with IC50 values of 13.10 ± 0.53, 16.02 ± 0.46, and 6.22 ± 0.54 µM, respectively. Moreover, these compounds are highly selective toward AChE. Compound 10i shows AChE inhibitory activity similar to a known Food and Drug Administration (FDA)-approved drug, galantamine, but with even better selectivity. Interaction analysis reveals that hydrophobic and hydrogen-bonding interactions are the primary driving forces responsible for the observed high affinity of the compound with AChE.

Comprehensive Characterization of Linalool-HP-ß-Cyclodextrin Inclusion Complexes.

The objective of the present study is to obtain linalool- cyclodextrin (CDs) solid complexes for possible applications in the food industry. For this purpose, a detailed study of linalool complexation was carried out at different pH values, to optimize the type of CDs and reaction medium that support the highest quantity of encapsulated linalool. Once demonstrated the ability of hydroxypropyl-ß-cyclodextrin (HP-ß-CDs), to form inclusion complexes with linalool (KC = 921 ± 21 L mol-1) and given their greater complexation efficacy (6.788) at neutral pH, HP-ß-CDs were selected to produce solid inclusion complexes by using two different energy sources, ultrasounds and microwave irradiation, subsequently spraying the solutions obtained in the Spray Dryer. To provide scientific solidity to the experimental results, the complexes obtained were characterized by using different instrumental techniques in order to confirm the inclusion of linalool in the HP-ß-CDs hydrophobic cavity. The linalool solid complexes obtained were characterized by using 1H nuclear magnetic resonance (1H-NMR) and 2D nuclear magnetic resonance (ROSEY), differential scanning calorimetry, thermogravimetry and Fourier transform infrared spectrometry. Moreover, the structure of the complex obtained were also characterized by molecular modeling.

Thorough characterization and stability of HP-ß-cyclodextrin thymol inclusion complexes prepared by microwave technology: A required approach to a successful application in food industry.

BACKGROUND: The aims of the present study were to obtain a stable dry powder formulation of cyclodextrins (CDs) encapsulating thymol, for successful use as an ingredient on an industrial scale, and to characterize the thymol-CDs complexes using different techniques. RESULTS: Thymol was successfully solubilized in aqueous solutions and the Kc value increased with the pH of the media until the pH was neutral, giving the highest values (2583 ± 176 L mol-1 ) for HP-ß-cyclodextrins (HP-ß-CDs). The best encapsulation efficiency of thymol in solid complexes was obtained using the microwave (MWI) encapsulation method. The different characterization techniques have demonstrated the affinity of HP-ß-CDs for thymol molecules, forming stable complexes. CONCLUSIONS: The results support the use of the MWI method in the preparation of solid HP-ß-CD-thymol complexes, due to greater encapsulation efficiency and technological and economic advantages for industrial applications. © 2018 Society of Chemical Industry.

Advances in distributed computing with modern drug discovery.

INTRODUCTION: Computational chemistry dramatically accelerates the drug discovery process and high-performance computing (HPC) can be used to speed up the most expensive calculations. Supporting a local HPC infrastructure is both costly and time-consuming, and, therefore, many research groups are moving from in-house solutions to remote-distributed computing platforms. Areas covered: The authors focus on the use of distributed technologies, solutions, and infrastructures to gain access to HPC capabilities, software tools, and datasets to run the complex simulations required in computational drug discovery (CDD). Expert opinion: The use of computational tools can decrease the time to market of new drugs. HPC has a crucial role in handling the complex algorithms and large volumes of data required to achieve specificity and avoid undesirable side-effects. Distributed computing environments have clear advantages over in-house solutions in terms of cost and sustainability. The use of infrastructures relying on virtualization reduces set-up costs. Distributed computing resources can be difficult to access, although web-based solutions are becoming increasingly available. There is a trade-off between cost-effectiveness and accessibility in using on-demand computing resources rather than free/academic resources. Graphics processing unit computing, with its outstanding parallel computing power, is becoming increasingly important.

Selective in vitro and in silico butyrylcholinesterase inhibitory activity of diterpenes and rosmarinic acid isolated from Perovskia atriplicifolia Benth. and Salvia glutinosa L.

Cholinesterase inhibition is one of the most treatment strategies against Alzheimer's disease (AD) where metal accumulation is also strongly associated with pathology of the disease. In the current study, we assessed inhibitory effect against acetyl- (AChE) and butyrylcholinesterase (BChE) and metal-chelating capacity of twelve diterpenes: arucadiol, miltirone, tanshinone IIa, 1-oxomiltirone, cryptotanshinone, 1,2-didehydromiltirone, 1,2-didehydrotanshinone IIa, 1ß-hydroxycryptotanshinone, 15,16-dihydrotanshinone, tanshinone I, isotanshinone II, 1(S)-hydroxytanshinone IIa, and rosmarinic acid, isolated from Perovskia atriplicifolia and Salvia glutinosa. The compounds were tested at 10 µg/mL using ELISA microtiter assays against AChE and BChE. QSAR and molecular docking studies have been also performed on the active compounds. All of the compounds showed higher [e.g., IC50 = 1.12 ± 0.07 µg/mL for 1,2-didehydromiltirone, IC50 = 1.15 ± 0.07 µg/mL for cryptotanshinone, IC50 = 1.20 ± 0.03 µg/mL for arucadiol, etc.)] or closer [1,2-didehydrotanshinone IIa (IC50 = 5.98 ± 0.49 µg/mL) and 1(S)-hydroxytanshinone IIa (IC50 = 5.71 ± 0.27 µg/mL)] inhibition against BChE as compared to that of galanthamine (IC50 = 12.56 ± 0.37 µg/mL), whereas only 15,16-dihydrotanshinone moderately inhibited AChE (65.17 ± 1.39%). 1,2-Didehydrotanshinone IIa (48.94 ± 0.26%) and 1(S)-hydroxytanshinone IIa (47.18 ± 5.10%) possessed the highest metal-chelation capacity. The present study affords an evidence for the fact that selective BChE inhibitors should be further investigated as promising candidate molecules for AD therapy.

Adherence to the "Mediterranean Diet" in Spain and Its Relationship with Cardiovascular Risk (DIMERICA Study).

BACKGROUND: Nutritional studies focus on traditional cultural models and lifestyles in different countries. The aim of this study was to examine the adherence to the Mediterranean diet, life habits, and risk factors associated with cardiovascular diseases among people living in different geographical regions in Spain. METHODS: A descriptive cross-sectional study was conducted in each region. The sampling scheme consisted of a random three-stage stratified sampling program according to geographic region, age, and gender. A total of 1732 subjects were asked to complete a questionnaire designed to assess their nutrient intake, dietary habits, and exercise. A diet score that assesses the adherence of participants to the Mediterranean diet (range 0-10) was also applied. RESULTS: Southeastern Spain had the lowest score for adherence to the Mediterranean diet because of the low consumption of fish and plant products. A lower adherence score to the Mediterranean diet was strongly associated with the prevalence of hypertension (p = 0.018). CONCLUSIONS: A low level of adherence to the Mediterranean diet is accompanied by a high prevalence of hypertension and, therefore, a raised cardiovascular risk in the country. The adherence score could help identify individuals at greater cardiovascular risk.

Latest QSAR study of adenosine Α2Β receptor affinity of xanthines and deazaxanthines.

Adenosine, a widespread and endogenous nucleoside that acts as a powerful neuromodulator in the nervous system, is a promising therapeutic target in a wide range of conditions. The structural similarity between xanthine derivatives and neurotransmitter adenosine has led to the derivatives of the heterocyclic ring being among the most abundant chemical classes of ligand antagonists of adenosine receptor subtypes. Small changes in the xanthine scaffold have resulted in a wide array of adenosine receptor antagonists. In this work, we developed a QSAR model for the [Formula: see text] subtype, which is, as yet, not well characterized, with two purposes in mind: to predict adenosine [Formula: see text] antagonist activity and to offer a substructural interpretation of this group of xanthines. The QSAR model provided good classifications of both the test and external sets. In addition, most of the contributions to adenosine [Formula: see text] receptor affinity derived by subfragmentation of the molecules in the training set agree with the relationships observed in the literature. These two factors mean that this QSAR ensemble could be used as a model to predict future adenosine [Formula: see text] antagonist candidates.

Combining QSAR classification models for predictive modeling of human monoamine oxidase inhibitors.

Due to their role in the metabolism of monoamine neurotransmitters, MAO-A and MAO-B present a significant pharmacological interest. For instance the inhibitors of human MAO-B are considered useful tools for the treatment of Parkinson Disease. Therefore, the rational design and synthesis of new MAOs inhibitors is considered of great importance for the development of new and more effective treatments of Parkinson Disease. In this work, Quantitative Structure Activity Relationships (QSAR) has been developed to predict the human MAO inhibitory activity and selectivity. The first step was the selection of a suitable dataset of heterocyclic compounds that include chromones, coumarins, chalcones, thiazolylhydrazones, etc. These compounds were previously synthesized in one of our laboratories, or elsewhere, and their activities measured by the same assays and for the same laboratory staff. Applying linear discriminant analysis to data derived from a variety of molecular representations and feature selection algorithms, reliable QSAR models were built which could be used to predict for test compounds the inhibitory activity and selectivity toward human MAO. This work also showed how several QSAR models can be combined to make better predictions. The final models exhibit significant statistics, interpretability, as well as displaying predictive power on an external validation set made up of chromone derivatives with unknown activity (that are being reported here for first time) synthesized by our group, and coumarins recently reported in the literature.

Topological sub-structural molecular design approach: radical scavenging activity.

In the last decades phenolic compounds have gained enormous interest because of their beneficial health effects such as anti-inflammatory, anticancer, or antiviral activities. The pharmacological effects of phenolic compounds are mainly due to their antioxidant activity and their inhibition of certain enzymes. This antoxidant activity is related to the structure and has been extensively reported throught SAR or QSAR models. These studies confirmed that the number and position of hydroxyl groups, the related glycosylation and other substitutions in the phenolic ring largely determined radical scavenging activity. Most of these models are based on certain families of chemicals (flavonoids, cinnamic acids, etc…) and the model by itself is not useful for other substances of a different family. In this study we developed a QSAR model for a heterogeneous group of substances with TOPS-MODE descriptors for an interpretation of the antioxidant activity of these compounds in the form of bond contributions. The model developed, able to describe more than 90% of the variance in the experimental activity, also has a good predictive ability and stability. The information extracted from the QSAR model revealed that the major driving forces for radical scavenging activity are hydrogen bond donation and polarity. With this work we have managed to unify the different families of antioxidants in a single model with sufficient capacity to make predictions of radical scavenging activity for unknown substances.

Two new parameters based on distances in a receiver operating characteristic chart for the selection of classification models.

There are several indices that provide an indication of different types on the performance of QSAR classification models, being the area under a Receiver Operating Characteristic (ROC) curve still the most powerful test to overall assess such performance. All ROC related parameters can be calculated for both the training and test sets, but, nevertheless, neither of them constitutes an absolute indicator of the classification performance by themselves. Moreover, one of the biggest drawbacks is the computing time needed to obtain the area under the ROC curve, which naturally slows down any calculation algorithm. The present study proposes two new parameters based on distances in a ROC curve for the selection of classification models with an appropriate balance in both training and test sets, namely the following: the ROC graph Euclidean distance (ROCED) and the ROC graph Euclidean distance corrected with Fitness Function (FIT(λ)) (ROCFIT). The behavior of these indices was observed through the study on the mutagenicity for four genotoxicity end points of a number of nonaromatic halogenated derivatives. It was found that the ROCED parameter gets a better balance between sensitivity and specificity for both the training and prediction sets than other indices such as the Matthews correlation coefficient, the Wilk's lambda, or parameters like the area under the ROC curve. However, when the ROCED parameter was used, the follow-on linear discriminant models showed the lower statistical significance. But the other parameter, ROCFIT, maintains the ROCED capabilities while improving the significance of the models due to the inclusion of FIT(λ).

QSAR models to predict mutagenicity of acrylates, methacrylates and alpha,beta-unsaturated carbonyl compounds.

OBJECTIVE: The purpose of this study is to develop a quantitative structure-activity relationship (QSAR) model that can distinguish mutagenic from non-mutagenic species with alpha,beta-unsaturated carbonyl moiety using two endpoints for this activity - Ames test and mammalian cell gene mutation test - and also to gather information about the molecular features that most contribute to eliminate the mutagenic effects of these chemicals. METHODS: Two data sets were used for modeling the two mutagenicity endpoints: (1) Ames test and (2) mammalian cells mutagenesis. The first one comprised 220 molecules, while the second one 48 substances, ranging from acrylates, methacrylates to alpha,beta-unsaturated carbonyl compounds. The QSAR models were developed by applying linear discriminant analysis (LDA) along with different sets of descriptors computed using the DRAGON software. RESULTS: For both endpoints, there was a concordance of 89% in the prediction and 97% confidentiality by combining the three models for the Ames test mutagenicity. We have also identified several structural alerts to assist the design of new monomers. SIGNIFICANCE: These individual models and especially their combination are attractive from the point of view of molecular modeling and could be used for the prediction and design of new monomers that do not pose a human health risk.

A topological substructural molecular design approach for predicting mutagenesis end-points of alpha, beta-unsaturated carbonyl compounds.

Chemically reactive, alpha, beta-unsaturated carbonyl compounds are common environmental pollutants able to produce a wide range of adverse effects, including, e.g. mutagenicity. This toxic property can often be related to chemical structure, in particular to specific molecular substructures or fragments (alerts), which can then be used in specialized software or expert systems for predictive purposes. In the past, there have been many attempts to predict the mutagenicity of alpha, beta-unsaturated carbonyl compounds through quantitative structure activity relationships (QSAR) but considering only one exclusive endpoint: the Ames test. Besides, even though those studies give a comprehensive understanding of the phenomenon, they do not provide substructural information that could be useful forward improving expert systems based on structural alerts (SAs). This work reports an evaluation of classification models to probe the mutagenic activity of alpha, beta-unsaturated carbonyl compounds over two endpoints--the Ames and mammalian cell gene mutation tests--based on linear discriminant analysis along with the topological Substructure molecular design (TOPS-MODE) approach. The obtained results showed the better ability of the TOPS-MODE approach in flagging structural alerts for the mutagenicity of these compounds compared to the expert system TOXTREE. Thus, the application of the present QSAR models can aid toxicologists in risk assessment and in prioritizing testing, as well as in the improvement of expert systems, such as the TOXTREE software, where SAs are implemented.

QSPR modelling with the topological substructural molecular design approach: beta-cyclodextrin complexation.

This study aims at developing a quantitative structure-property relationship (QSPR) model for predicting complexation with beta-cyclodextrins (beta-CD) based on a large variety of organic compounds. Molecular descriptors were computed following the TOPological Substructural MOlecular DEsign (TOPS-MODE) approach and correlated with beta-CD complex stability constants by linear multivariate data analysis. This strategy afforded a final QSPR model that was able to explain around 86% of the variance in the experimental activity, along with showing good internal cross-validation statistics, and also good predictivity on external data. Topological substructural information influencing the complexation with beta-CD was extracted from the QSPR model. This revealed that the major driving forces for complexation are hydrophobicity and van der Waals interactions. Therefore, the presence of hydrophobic groups (hydrocarbon chains, aryl groups, etc.) and voluminous species (Cl, Br, I, etc.) in the molecules renders easy their complexity with beta-CDs. To our knowledge, this is the first time a correlation between TOPS-MODE descriptors and complexing abilities of beta-CDs has been reported.

Convenient QSAR model for predicting the complexation of structurally diverse compounds with beta-cyclodextrins.

This paper reports a QSAR study for predicting the complexation of a large and heterogeneous variety of substances (233 organic compounds) with beta-cyclodextrins (beta-CDs). Several different theoretical molecular descriptors, calculated solely from the molecular structure of the compounds under investigation, and an efficient variable selection procedure, like the Genetic Algorithm, led to models with satisfactory global accuracy and predictivity. But the best-final QSAR model is based on Topological descriptors meanwhile offering a reasonable interpretation. This QSAR model was able to explain ca. 84% of the variance in the experimental activity, and displayed very good internal cross-validation statistics and predictivity on external data. It shows that the driving forces for CD complexation are mainly hydrophobic and steric (van der Waals) interactions. Thus, the results of our study provide a valuable tool for future screening and priority testing of beta-CDs guest molecules.