Latest advances in molecular topology applications for drug discovery

Introduction: Molecular topology (MT) has emerged in recent years as a powerful approach for the in silico generation of new drugs. In the last decade, its application has become more and more popular among the leading research groups in the field of quantitative structure--activity relationships (QSAR) and drug design. This has, in turn, contributed to the rapid development of new techniques and applications of MT in QSAR studies, as well as the introduction of new topological indices. Areas covered: This review collates the main innovative techniques in the field of MT and provides a description of the novel topological indices recently introduced, through an exhaustive recompilation of the most significant works carried out by the leading research groups in the field of drug design and discovery. The objective is to show the importance of MT methods combined with the effectiveness of the descriptors. Expert opinion: Recent years have witnessed a remarkable rise in QSAR methods based on MTand its application to drug design. New methodologies have been introduced in the area such as QSAR multi-target, Markov networks or perturbation methods. Moreover, novel topological indices, such as Bourgas’ descriptors and other new concepts as the derivative of a graph or cliques capable to distinguish between conformers, have also been introduced. New drugs have also been discovered, including anticonvulsants, anineoplastics, antimalarials or antiallergics, just to name a few. In the authors’ opinion, MT and QSAR have moved from an attractive possibility to representing a foundation stone in the process of drug discovery

Molecular Topology Applied to the Discovery of 1-Benzyl-2-(3-fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2 H

We report the discovery of 1-benzyl-2-(3-fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2H-pyrrole-5-one as a novel non-ligand binding pocket (non-LBP) antagonist of the androgen receptor (AR) through the application of molecular topology techniques. This compound, validated through time-resolved fluorescence resonance energy transfer and fluorescence polarization biological assays, provides the basis for lead optimization and structure−activity relationship analysis of a new series of non-LBP AR antagonists. Induced-fit docking and molecular dynamics studies have been performed to establish a consistent hypothesis for the interaction of the new active molecule on the AR surface

Discovery of novel anti-inflammatory drug-like compounds by aligning in silico and in vivo screening: The nitroindazolinone chemotype

In this report, we propose the combination of computational methods and in vivo primary screening in zebrafish larvae and confirmatory in mice models as a novel strategy to accelerate anti-inflammatory drug discovery. Initially, a database of 1213 organic chemicals with great structural variability - 587 of them anti-inflammatory agents plus 626 compounds with other clinical uses - was divided into training and test groups. Atom-based quadratic indices - a TOMOCOMD-CARDD molecular descriptors family - and linear discriminant analysis (LDA) were used to develop a total of 13 models to describe the anti-inflammatory activity. The best model (Eq. (13)) shows an accuracy of 87.70% in the training set, and values of Matthews correlation coefficient (C) of 0.75. The robustness of the models was demonstrated using an external test set as validation method, i.e., Eq. (13) revealing classification of 88.44% (C = 0.77) in this series. All models were employed to develop ensemble a QSAR classification system, in which the individual QSAR outputs are the inputs of the aforementioned fusion approach. The fusion model was used for the identification of novel anti-inflammatory compounds using virtual screening of 145 molecules available in our in-house library of indazole, indole, cinnoline and quinoxaline derivatives. Out of these, 34 chemicals were selected, synthesized and tested in a lipopolysaccharide (LPS)-induced leukocyte migration assay in zebrafish larvae. This activity was evaluated based on leukocyte migration to the injury zone of tail-transected larvae. Compounds 18 (3 μM), 24 (10 μM), 25 (10 μM), 6 (10 μM), 15 (30 μM), 11 (30 μM) and 12 (30 μM) gave the best results displaying relative leukocyte migration (RLM) values of 0.24, 0.27, 0.35, 0.41, 0.17, 0. 26 and 0.27 respectively, date that suggest an anti-inflammatory activity of 76, 73, 65, 59, 83, 84 and 73%, respectively. Compound 18 was the most potent but showed high toxicity together with compound 6. Next, we used the tetradecanoylphorbol acetate (TPA)-induced mouse ear oedema model to evaluate the most potent compounds in the zebrafish larvae tail transection assay. All assayed compounds, with the exception of chemical 15, showed anti-inflammatory activity in mice. Compound 12 (VA5-13l, 2-benzyl-1-methyl-5-nitro-1,2-dihydro-3H-indazol-3-one) was the most active and completely abolished the oedema. Compounds 6, 11 and 24 showed inhibition percentages in the range of the reference drug (indomethacin), whereas compounds 18 and 25 reduced the oedema in a lesser extent (inhibition of 73 and 80%, respectively). In addition, all compounds except chemical 15, significantly reduced neutrophil infiltration, measured as myeloperoxidase activity on TPA application test. Compounds 6, 11, 12 and 18 showed values comparable to indomethacin (inhibition percentage of 61), but compounds 6 and 18 were toxic in zebrafish and showed unspecific cytotoxicity in murine macrophages at 100 μg/mL, while the remaining compounds 11, 12 and 25 were inactive at most levels. Evidently, this study suggests a new support structure (12, 11 and 24; a nitroindazolinone chemotype) that constitutes a novel promising lead and may represent an important therapeutic alternative for the treatment of inflammatory conditions. © 2011 Elsevier Masson SAS. All rights reserved.The authors acknowledge also the partial financial support from Ministerio de Ciencia e Innovacion de España (Projects SAF2009-10399, SAF2009-13059-C03-01 and SAF2009-13059-C03- 02). Also, this work was supported in part by VLIR (Vlaamse InterUniversitaire Raad, Flemish Interuniversity Council, Belgium) under the IUC Program VLIR-UCLV. Finally, but not least, the authors want to express their acknowledgements to Prof. Luis Rios for his availability to experimental tests at the VU and to Prof. Jorge Galvez (VU) for his help and useful comments about the new chemicals.Peer Reviewe

Modeling Drug-Induced Anorexia by Molecular Topology

Molecular topology (MT) has demonstrated to be a very good technique for describing molecular structures and to predict physical, chemical, and biological properties of compounds. In this paper, a topological−mathematical model based on MT has been developed for identifying drug compounds showing anorexia as a side effect. An external validation (test set) has been carried out, yielding over an 80% correct classification in the active and inactive compounds. These results reinforce the role of MT as a potential useful tool for predicting drug side effects