Alejandro Speck-Planche

Computational tool for risk assessment of nanomaterials: novel QSTR-perturbation model for simultaneous prediction of ecotoxicity and cytotoxicity of uncoated and coated nanoparticles under multiple experimental conditions.

Nanomaterials have revolutionized modern science and technology due to their multiple applications in engineering, physics, chemistry, and biomedicine. Nevertheless, the use and manipulation of nanoparticles (NPs) can bring serious damages to living organisms and their ecosystems. For this reason, ecotoxicity and cytotoxicity assays are of special interest in order to determine the potential harmful effects of NPs. Processes based on ecotoxicity and cytotoxicity tests can significantly consume time and financial resources. In this sense, alternative approaches such as quantitative structure-activity/toxicity relationships (QSAR/QSTR) modeling have provided important insights for the better understanding of the biological behavior of NPs that may be responsible for causing toxicity. Until now, QSAR/QSTR models have predicted ecotoxicity or cytotoxicity separately against only one organism (bioindicator species or cell line) and have not reported information regarding the quantitative influence of characteristics other than composition or size. In this work, we developed a unified QSTR-perturbation model to simultaneously probe ecotoxicity and cytotoxicity of NPs under different experimental conditions, including diverse measures of toxicities, multiple biological targets, compositions, sizes and conditions to measure those sizes, shapes, times during which the biological targets were exposed to NPs, and coating agents. The model was created from 36488 cases (NP-NP pairs) and exhibited accuracies higher than 98% in both training and prediction sets. The model was used to predict toxicities of several NPs that were not included in the original data set. The results of the predictions suggest that the present QSTR-perturbation model can be employed as a highly promising tool for the fast and efficient assessment of ecotoxicity and cytotoxicity of NPs.

Rational drug design for anti-cancer chemotherapy: multi-target QSAR models for the in silico discovery of anti-colorectal cancer agents.

The discovery of new and more potent anti-cancer agents constitutes one of the most active fields of research in chemotherapy. Colorectal cancer (CRC) is one of the most studied cancers because of its high prevalence and number of deaths. In the current pharmaceutical design of more efficient anti-CRC drugs, the use of methodologies based on Chemoinformatics has played a decisive role, including Quantitative-Structure-Activity Relationship (QSAR) techniques. However, until now, there is no methodology able to predict anti-CRC activity of compounds against more than one CRC cell line, which should constitute the principal goal. In an attempt to overcome this problem we develop here the first multi-target (mt) approach for the virtual screening and rational in silico discovery of anti-CRC agents against ten cell lines. Here, two mt-QSAR classification models were constructed using a large and heterogeneous database of compounds. The first model was based on linear discriminant analysis (mt-QSAR-LDA) employing fragment-based descriptors while the second model was obtained using artificial neural networks (mt-QSAR-ANN) with global 2D descriptors. Both models correctly classified more than 90% of active and inactive compounds in training and prediction sets. Some fragments were extracted from the molecules and their contributions to anti-CRC activity were calculated using mt-QSAR-LDA model. Several fragments were identified as potential substructural features responsible for the anti-CRC activity and new molecules designed from those fragments with positive contributions were suggested and correctly predicted by the two models as possible potent and versatile anti-CRC agents.

Chemoinformatics in anti-cancer chemotherapy: Multi-target QSAR model for the in silico discovery of anti-breast cancer agents

The discovery of new and more efficient anti-cancer chemotherapies is a field of research in expansion and growth. Breast cancer (BC) is one of the most studied cancers because it is the principal cause of cancer deaths in women. In the active area for the search of more potent anti-BC drugs, the use of approaches based on Chemoinformatics has played a very important role. However, until now there is no methodology able to predict anti-BC activity of compounds against more than one BC cell line, which should constitute a greater interest. In this study we introduce the first chemoinformatic multi-target (mt) approach for the in silico design and virtual screening of anti-BC agents against 13 cell lines. Here, an mt-QSAR discriminant model was developed using a large and heterogeneous database of compounds. The model correctly classified 88.47% and 92.75% of active and inactive compounds respectively, in training set. The validation of the model was carried out by using a prediction set which showed 89.79% of correct classification for active and 92.49% for inactive compounds. Some fragments were extracted from the molecules and their contributions to anti-BC activity were calculated. Several fragments were identified as potential substructural features responsible for anti-BC activity and new molecules designed from those fragments with positive contributions were suggested as possible potent and versatile anti-BC agents.

Predicting multiple ecotoxicological profiles in agrochemical fungicides: a multi-species chemoinformatic approach.

Agriculture is needed to deal with crop losses caused by biotic stresses like pests. The use of pesticides has played a vital role, contributing to improve crop production and harvest productivity, providing a better crop quality and supply, and consequently contributing with the improvement of the human health. An important group of these pesticides is fungicides. However, the use of these agrochemical fungicides is an important source of contamination, damaging the ecosystems. Several studies have been realized for the assessment of the toxicity in agrochemical fungicides, but the principal limitation is the use of structurally related compounds against usually one indicator species. In order to overcome this problem, we explore the quantitative structure-toxicity relationships (QSTR) in agrochemical fungicides. Here, we developed the first multi-species (ms) chemoinformatic approach for the prediction multiple ecotoxicological profiles of fungicides against 20 indicators species and their classifications in toxic or nontoxic. The ms-QSTR discriminant model was based on substructural descriptors and a heterogeneous database of compounds. The percentages of correct classification were higher than 90% for both, training and prediction series. Also, substructural alerts responsible for the toxicity/no toxicity in fungicides respect all ecotoxicological profiles, were extracted and analyzed.

Multi-target drug discovery in anti-cancer therapy: Fragment-based approach toward the design of potent and versatile anti-prostate cancer agents

Prostate cancer (PCa) is the second-leading cause of cancer deaths among men in the around the world. Understanding the biology of PCa is essential to the development of novel therapeutic strategies, in order to prevent this disease. However, after PCa make metastases, chemotherapy plays an extremely important role. With the pass of the time, PCa cell lines become resistant to the current anti-PCa drugs. For this reason, there is a necessity to develop new anti-PCa agents with the ability to be active against several PCa cell lines. The present work is an effort to overcome this problem. We introduce here the first multi-target approach for the design and prediction of anti-PCa agents against several cell lines. Here, a fragment-based QSAR model was developed. The model had a sensitivity of 88.36% and specificity 89.81% in training series. Also, the model showed 94.06% and 92.92% for sensitivity and specificity, respectively. Some fragments were extracted from the molecules and their contributions to anti-PCa activity were calculated. Several fragments were identified as potential substructural features responsible of anti-PCa activity and new molecular entities designed from fragments with positive contributions were suggested as possible anti-PCa agents.

Computational ecotoxicology: simultaneous prediction of ecotoxic effects of nanoparticles under different experimental conditions.

Nanotechnology has brought great advances to many fields of modern science. A manifold of applications of nanoparticles have been found due to their interesting optical, electrical, and biological/chemical properties. However, the potential toxic effects of nanoparticles to different ecosystems are of special concern nowadays. Despite the efforts of the scientific community, the mechanisms of toxicity of nanoparticles are still poorly understood. Quantitative-structure activity/toxicity relationships (QSAR/QSTR) models have just started being useful computational tools for the assessment of toxic effects of nanomaterials. But most QSAR/QSTR models have been applied so far to predict ecotoxicity against only one organism/bio-indicator such as Daphnia magna. This prevents having a deeper knowledge about the real ecotoxic effects of nanoparticles, and consequently, there is no possibility to establish an efficient risk assessment of nanomaterials in the environment. In this work, a perturbation model for nano-QSAR problems is introduced with the aim of simultaneously predicting the ecotoxicity of different nanoparticles against several assay organisms (bio-indicators), by considering also multiple measures of ecotoxicity, as well as the chemical compositions, sizes, conditions under which the sizes were measured, shapes, and the time during which the diverse assay organisms were exposed to nanoparticles. The QSAR-perturbation model was derived from a database containing 5520 cases (nanoparticle-nanoparticle pairs), and it was shown to exhibit accuracies of ca. 99% in both training and prediction sets. In order to demonstrate the practical applicability of our model, three different nickel-based nanoparticles (Ni) with experimental values reported in the literature were predicted. The predictions were found to be in very good agreement with the experimental evidences, confirming that Ni-nanoparticles are not ecotoxic when compared with other nanoparticles. The results of this study thus provide a single valuable tool toward an efficient prediction of the ecotoxicity of nanoparticles under multiple experimental conditions.

In Silico Discovery and Virtual Screening of Multi-Target Inhibitors for Proteins in Mycobacterium tuberculosis

Mycobacterium tuberculosis (MTB) is the principal pathogen which causes tuberculosis (TB), a disease that remains as one of the most alarming health problems worldwide. An active area for the search of new anti-TB therapies is concerned with the use of computational approaches based on Chemoinformatics and/or Bioinformatics toward the discovery of new and potent anti-TB agents. These approaches consider only small series of structurally related compounds and the studies are generally realized for only one target like a protein. This fact constitutes an important limitation. The present work is an effort to overcome this problem. We introduce here the first chemo-bioinformatic approach by developing a multi-target (mt) QSAR discriminant model, for the in silico design and virtual screening of anti-TB agents against six proteins in MTB. The mt-QSAR model was developed by employing a large and heterogeneous database of compounds and substructural descriptors. The model correctly classified more than 90% of active and inactive compounds in both, training and prediction series. Some fragments were extracted from the molecules and their contributions to anti-TB activity through inhibition of the six proteins, were calculated. Several fragments were identified as responsible for anti-TB activity and new molecular entities were designed from those fragments with positive contributions, being suggested as possible anti-TB agents.

New insights toward the discovery of antibacterial agents: Multi-tasking QSBER model for the simultaneous prediction of anti-tuberculosis activity and toxicological profiles of drugs

Tuberculosis (TB) constitutes one of the most dangerous and serious health problems around the world. It is a very lethal disease caused by microorganisms of the genus mycobacterium, principally Mycobacterium tuberculosis (MTB) which affects humans. A very active field for the search of more efficient anti-TB chemotherapies is the use in silico methodologies for the discovery of potent anti-TB agents. The battle against MTB by using antimicrobial chemotherapies will depend on the design of new chemicals with high anti-TB activity and low toxicity as possible. Multi-target methodologies focused on quantitative-structure activity relationships (mt-QSAR) have played a very important role for the rationalization of drug design, providing a better understanding about the molecular patterns related with diverse pharmacological profiles including antimicrobial activity. Nowadays, almost all mt-QSAR models have considered the study of biological activity or toxicity separately. In the present study, we develop by the first time, a unified multitasking model based on quantitative-structure biological effect relationships (mtk-QSBER) for the simultaneous prediction of anti-TB activity and toxicity against Mus musculus and Rattus norvegicus. The mtk-QSBER model was created by using linear discriminant analysis (LDA) for the classification of compounds as positive (high biological activity and/or low toxicity) or negative (otherwise) under many experimental conditions. Our mtk-QSBER model, correctly classified more than 90% of the case in the whole database (more than 12,000 cases), serving as a powerful tool for the computer-assisted screening of potent and safe anti-TB drugs.

Chemoinformatics in multi-target drug discovery for anti-cancer therapy: in silico design of potent and versatile anti-brain tumor agents.

A brain tumor (BT) constitutes a neoplasm located in the brain or the central spinal canal. The number of new diagnosed cases with BT increases with the pass of the time. Understanding the biology of BT is essential for the development of novel therapeutic strategies, in order to prevent or deal with this disease. An active area for the search of new anti-BT therapies is the use of Chemoinformatics and/or Bioinformatics toward the design of new and potent anti-BT agents. The principal limitation of all these approaches is that they consider small series of structurally related compounds and/or the studies are realized for only one target like protein. The present work is an effort to overcome this problem. We introduce here the first Chemoinformatics multi-target approach for the in silico design and prediction of anti-BT agents against several cell lines. Here, a fragment-based QSAR model was developed. The model correctly classified 89.63% and 90.93% of active and inactive compounds respectively, in training series. The validation of the model was carried out by using prediction series which showed 88.00% of correct classification for active and 88.59% for inactive compounds. Some fragments were extracted from the molecules and their contributions to anti-BT activity were calculated. Several fragments were identified as potential substructural features responsible of anti-BT activity and new molecular entities designed from fragments with positive contributions were suggested as possible anti-BT agents.

Fragment-based QSAR model toward the selection of versatile anti-sarcoma leads

A sarcoma is a type of cancer which is originated from the connective tissue cells. With the time, several sarcomas have become resistant to the current anti-tumoral drugs. Many works have been reported in order to explain some mechanisms of resistance in different types of sarcomas and around 2000 compounds have been tested as anti-sarcoma agents against several sarcoma cell lines. However, there is no an available methodology for the rational design of compounds with anti-sarcoma activity. The present work develops a unified fragment-based approach by employing a multi-target QSAR model for the efficient search and design of new anti-sarcoma agents against 12 sarcoma cell lines. The model was obtained with the use of a heterogeneous database of compounds and it was based on substructural descriptors. The percentages of correct classification of active and inactive compounds were higher than 85% in both cases. Also, the present approach provided the rapid extraction of substructural alerts responsible of anti-sarcoma profile by calculating the quantitative contributions of fragments to anti-sarcoma activity. To our knowledge, this is the first attempt to calculate the probabilities of anti-sarcoma activity of compounds against several sarcoma cell lines simultaneously, using a unified fragment-based QSAR model.