Desenvolupament del programari ArIS (Artificial Intelligence Suite): implementació d’eines de cribratge virtual per a la química mèdica

El disseny molecular de sistemes d’interès per a la química mèdica i per al disseny de fàrmacs sempre s’ha trobat molt lligat a la disponibilitat sintètica dels resultats. Des del moment que la química combinatòria s’incorpora dins de l’esquema sintètic, canvia el paper que ha de jugar la química computacional: la diversitat d’estructures possibles a sintetitzar fa necessària la introducció de mètodes, com el cribratge virtual, que permetin avaluar la viabilitat de grans quimioteques virtuals amb un temps raonable. Els mètodes quimioinformàtics responen a la necessitat anterior, posant a l’abast de l’usuari mètodes eficaços per a la predicció teòrica d’activitats biològiques o propietats d’interès. Dins d’aquests destaquen els mètodes basats en la relació quantitativa d’estructura-activitat (QSAR). Aquests han demostrat ser eficaços per l’establiment de models de predicció en l’àmbit farmacològic i biomèdic. S’ha avaluat la utilització de mètodes QSAR no lineals en la teràpia fotodinàmica del càncer, donat que és una de les línies de recerca d’interès del Grup d’Enginyeria Molecular (GEM) de l’IQS. El disseny de fotosensibilitzadors es pot realitzar a partir de la predicció de propietats fisicoquímiques (com l’espectre d’absorció i la hidrofobicitat del sistema molecular), i de l’estudi de la seva localització subcel•lular preferent, la qual ha demostrat recentment jugar un paper molt important en l’eficàcia del procés global. Per altra banda, les xarxes neuronals artificials són actualment un dels mètodes més ben valorats per a l’establiment de models QSAR no lineals. Donat l’interès de disposar d’un programari capaç d’aplicar aquests mètodes i que, a més, sigui prou versàtil i adaptable com per poder-se aplicar a diferents problemes, s’ha desenvolupat el programari ArIS. Aquest inclou els principals mètodes de xarxes neuronals artificials, per realitzar tasques de classificació i predicció quantitativa, necessaris per a l’estudi de problemes d’interès, com és la predicció de l’activitat anti-VIH d’anàlegs de l’AZT, l’optimització de formulacions químiques o el reconeixement estructural de grans sistemes molecularsEl diseño molecular de sistemas de interés para la química médica y para el diseño de fármacos siempre ha estado condicionado por la disponibilidad sintética de los resultados. Desde el momento en que la química combinatoria se incorpora en el esquema sintético, cambia el papel de la química computacional: la diversidad de estructuras que pueden sintetizarse hace necesaria la introducción de métodos, como el cribado virtual, que permitan evaluar la viabilidad de grandes quimiotecas virtuales en un tiempo razonable. Los métodos quimioinformáticos responden a la necesidad anterior, ofreciendo al usuario métodos eficaces para la predicción teórica de actividades biológicas o propiedades de interés. Entre ellos destacan los métodos basados en la relación cuantitativa de estructura-actividad (QSAR), que han demostrado ser eficaces para establecer modelos de predicción en el ámbito farmacológico y biomédico. Se ha evaluado la utilización de métodos QSAR no lineales en terapia fotodinámica del cáncer, dado que es una de las líneas de investigación de interés del Grup d’Enginyeria Molecular (GEM) del IQS. El diseño de fotosensibilizadores se puede realizar a partir de la predicción de propiedades fisicoquímicas (como su espectro de absorción o su hidrofobicidad) y del estudio de su localización subcelular preferente, la cual ha demostrado recientemente jugar un papel muy importante en la eficacia del proceso global. Por otro lado, las redes neuronales artificiales son actualmente uno de los métodos mejor valorados para establecer modelos QSAR no lineales. Es por ello que resulta muy interesante disponer de un programa capaz de aplicar estos métodos y que, además, sea lo suficientemente versátil y adaptable como para poder aplicarse a distintos problemas, según las necesidades del usuario. Por este motivo se ha desarrollado el programa ArIS, el cual incluye los principales métodos de redes neuronales artificiales para realizar tareas de clasificación y predicción cuantitativa, necesarios para el estudio de problemas de interés como la predicción de la actividad anti-VIH de análogos del AZT, la optimización de formulaciones químicas o el reconocimiento estructural de grandes sistemas moleculares.Molecular modelling of interesting systems for medicinal chemistry and drug design highly depends on availability of synthetic results. Since combinatorial chemistry was incorporated into the synthetic scheme, the role of computational chemistry has changed: the structural diversity of candidates to be synthesized requires the introduction of computational methods which are able to screen large virtual libraries. Answering to this requirement, chemoinformatics offers many kinds of different methods for predicting biological activities and molecular properties. One of the most relevant techniques among them is Quantitative Structure-Activity Relationships (QSAR), which can be used to establish prediction models for both, pharmacological and biomedical sectors. The use of non- linear QSAR methods has been evaluated in photodynamic therapy of cancer, one of the research areas of the Grup d’Enginyeria Molecular (GEM) at IQS. Molecular design of photosensitizers can be performed by computational studies of their physicochemical properties (absorption spectra or hydrophobicity, for example) and subcellular localization, which becomes a key factor in the efficacy of the overall process. Furthermore, artificial neural networks are nowadays rated as one of the very best methods for establishing non-linear QSAR models. Developing software that includes all these methods would be certainly interesting. Implemented algorithms should be versatile and easily adaptable for their use in any problems. We have developed ArIS software, which includes the most important methods of artificial neural networks for classification and quantitative prediction. ArIS has been used to predict anti-HIV activity of AZT-analogues, for optimization of chemical formulations and for structural recognition in large molecular systems, among others

Multiscale modeling for complex chemical systems: Highlights about the Nobel Prize in Chemistry 2013

The Nobel Prize in Chemistry 2013 was awarded jointly to Martin Karplus, Michael Levitt and Arieh Warshel for the development of multiscale models for complex chemical systems. From the simplest approximation of molecular mechanics (MM) to quantum mechanics (QM), computational techniques allow simulating a great variety ofchemical systems. Combined QM/MM methodologies, however, are the best consensus for treating complex biological systems. Herein we review the theoretical basis of QM/MM methods and their applications during the last twenty years.

Octanol-water partition coefficients of highly hydrophobic photodynamic therapy drugs: a computational study

Photodynamic therapy is a novel treatment for solid tumorsbased on the selective induction of cell death by the generation of cytotoxic reactive oxygen species within neoplastic tissues. Oxygen photosensitization is promoted as a consequence of the activation (using light) of a photosensitizer, which must reach the desired tissue by cellular transport. Hydrophobicity (expressed as the logarithm of octanol/water partition coefficient, logP), becomes a key factor in these processes. Unfortunately, there is no computational method to unambiguously predict the logP value for high hydrophobic photosensitizers. In this study, a total of 12 computational methods have been tested for predicting the logP value of tetrapyrrolic derivatives. Furthermore, in the attempt to correlate logP with experimental HPLC measurements (log(k’)), validation of the results leads to the proposal of a sigmoidal regression for the two parameters (log(k’) and logP)

Analysis of laccase-like enzymes secreted by fungi isolated from a cave in northern Spain

[EN] Laccases belong to a family of multicopper enzymes able to oxidize a broad spectrum of organic compounds. Despite the well-known property of laccases to carry out bleaching and degradation of industrial dyes and polyphenolic compounds, their industrial use is often limited by the high cost, low efficiency, or instability of these enzymes. To look for new microorganisms which produce laccases that are potentially suitable for industrial applications, we have isolated several fungal strains from a cave in northern Spain. Their phenotypic analysis on agar plates supplemented with ABTS (2,2 '-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) disclosed two laccase-positive strains. Further genotyping revealed that they belonged to the Gliomastix murorum and Conidiobolus thromboides species. The secretion of G. murorum and C. thromboides laccase-like enzymes was then confirmed by zymography. Further identification of these polypeptides by mass-spectroscopy revealed the nature of the laccases and made it possible to predict their functional domains and other features. In addition, plate assays revealed that the laccases secreted by both G. murorum and C. thromboides were capable of degrading industrial dyes (Congo Red, Indigo, and Eriochrome Black T). Homology modeling and substrate docking predicted the putative structure of the currently uncrystallized G. murorum enzyme as well as its amino acid residues potentially involved in interactions with these dyes. In summary, new biochemical and structural insights into decolorization mediated by G. murorum laccase as well as identification of laccase-like oxidase in C. thromboides point to a promising future for these enzymes in biotechnology.AIOTEK, Grant/Award Number: SPE12UN84; Basque Foundation for Science; Basque Government, Grant/Award Number: PRE-2013-1-90

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (' flakka') Derivatives

Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted -PVP derivatives. Thus, the aim of this study was to investigate the role of para- and meta-halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of -pyrrolidinopentiophenone ( - PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. Meta-substituted cathinones showed higher DAT/SERT ratios than their para- analogs, which correlates with an increased psychostimulant effect in vivo and with different meta- and para-in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of meta- and para-halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated -PVP derivatives

C4-C5 fused pyrazol-3-amines: when the degree of unsaturation and electronic characteristics of the fused ring controls regioselectivity in Ullmann and acylation reactions

Pyrazol-3-amine is a scaffold present in a large number of compounds with a wide range of biological activities and, in many cases, the heterocycle is C4-C5 fused to a second ring. Among the different reactions used for the decoration of the pyrazole ring, Ullmann and acylation have been widely applied. However, there is some confusion in the literature regarding the regioselectivity of such reactions (substitution at N1 or N2 of the pyrazole ring) and no predictive rule has been so far established. As a part of our work on 3-amino-pyrazolo[3,4-b]pyridones 13, we have studied the regioselectivity of such reactions in different C4-C5 fused pyrazol-3-amines. As a rule of thumb, the Ullmann and acylation reactions take place, predominantly, at the NH and non-protonated nitrogen atom of the pyrazole ring respectively, of the most stable initial tautomer (1H- or 2H-pyrazole), which can be easily predicted by using DFT calculations

An Unequivocal Synthesis of 2-Aryl Substituted 3-Amino-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-ones

The reaction between pyridones (1) and substituted hydrazines 4 can afford two different regioisomeric pyrazolo[3,4-b]pyridin - 6-ones 2 and 3 depending on the initial substitution of the methoxy group and the direction of the cyclization. In the case of phenylhydrazine 4 (R3 = Ph), we have clearly shown that the treatment of pyridones 1a-d with 4 (R3 = Ph) in MeOH at temperatures below 1408C yields, independently of the nature and position of the substituents present in the pyridone ring, the open intermediates 7a-d. When the reaction is carried at 1408C under microwave irradiation, the corresponding 2-aryl substituted pyrazolo[3,4-b]pyridines 3a-d are always formed. We have experimentally determined, using DSC techniques, the activation energies of the two steps involved in the formation of 3: a) substitution of the methoxy group present in pyridones 1 with phenylhydrazine 4 (R3 = Ph) to afford intermediates 7 and b) cyclization of intermediates 7 to yield pyrazolopyridines 3. The results obtained, 15 and 42 kcal·mol 1 respectively, are in agreement with the experimental findings

Breu introducció a la digitalització de la informació química

La informació química, que tradicionalment s'havia gestionat a través de llibres, paradigmàticament, a través del Chemical Abstracts Service i dels diversos handbooks, ha migrat progressivament a la xarxa. Actualment, a la xarxa hi ha grans bases de dades, tant comercials com d'accés gratuït, que contenen molta més informació de la que mai hem tingut a l'abast. Però accedir-hi requereix assolir algunes destreses que fins ara no han trobat un lloc en els estudis oficials de l'àmbit de la química. Aquest article presenta una breu introducció a les notacions i codis que s'usen per identificar les espècies químiques en entorns informàtics, al mateix temps que s'hi mostren algunes de les bases de dades d'informació química que són accessibles de forma gratuïta.Chemical information, once managed in books, paradigmatically in Chemical Abstracts Service and several handbooks, has now migrated to the Internet. Nowadays, many large databases, both commercial and freely available, have much more information than we have ever had. But accessing them requires some skills that are not yet taught in the official chemistry degrees. This paper presents a brief introduction to the notations and codes that are currently used to identify the chemical species in computer environments. At the same time, some freely available chemistry databases are presented

Deconstructing Markush: Improving the R&D Efficiency Using Library Selection in Early Drug Discovery

Most of the product patents claim a large number of compounds based on a Markush structure. However, the identification and optimization of new principal active ingredients is frequently driven by a simple Free Wilson approach, leading to a highly focused study only involving the chemical space nearby a hit compound. This fact raises the question: do the tested compounds described in patents really reflect the full molecular diversity described in the Markush structure? In this study, we contrast the performance of rational selection to conventional approaches in seven real-case patents, assessing their ability to describe the patent’s chemical space. Results demonstrate that the integration of computer-aided library selection methods in the early stages of the drug discovery process would boost the identification of new potential hits across the chemical space