E. V. Radchenko

Virtual computational chemistry laboratory - design and description

Internet technology offers an excellent opportunity for the development of tools by the cooperative effort of various groups and institutions. We have developed a multi-platform software system, Virtual Computational Chemistry Laboratory, http://www.vcclab.org, allowing the computational chemist to perform a comprehensive series of molecular indices/properties calculations and data analysis. The implemented software is based on a three-tier architecture that is one of the standard technologies to provide client-server services on the Internet. The developed software includes several popular programs, including the indices generation program, DRAGON, a 3D structure generator, CORINA, a program to predict lipophilicity and aqueous solubility of chemicals, ALOGPS and others. All these programs are running at the host institutes located in five countries over Europe. In this article we review the main features and statistics of the developed system that can be used as a prototype for academic and industry models.

Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information.

The Online Chemical Modeling Environment is a web-based platform that aims to automate and simplify the typical steps required for QSAR modeling. The platform consists of two major subsystems: the database of experimental measurements and the modeling framework. A user-contributed database contains a set of tools for easy input, search and modification of thousands of records. The OCHEM database is based on the wiki principle and focuses primarily on the quality and verifiability of the data. The database is tightly integrated with the modeling framework, which supports all the steps required to create a predictive model: data search, calculation and selection of a vast variety of molecular descriptors, application of machine learning methods, validation, analysis of the model and assessment of the applicability domain. As compared to other similar systems, OCHEM is not intended to re-implement the existing tools or models but rather to invite the original authors to contribute their results, make them publicly available, share them with other users and to become members of the growing research community. Our intention is to make OCHEM a widely used platform to perform the QSPR/QSAR studies online and share it with other users on the Web. The ultimate goal of OCHEM is collecting all possible chemoinformatics tools within one simple, reliable and user-friendly resource. The OCHEM is free for web users and it is available online at http://www.ochem.eu.

Molecular Field Topology Analysis Method in QSAR Studies of Organic Compounds

A new method of QSAR analysis for organic compounds, molecular field topology analysis (MFTA), is considered that involves the topological superposition of the training set structures and the construction of a molecular supergraph (MSG). This enables the creation of the uniform descriptor vectors based on the local physicochemical parameters (atom and bond properties) of the molecules. The application of this technique is illustrated by a number of examples, and its features are discussed. The MFTA is especially suitable for solving the problems where the analysis of three-dimensional structure is either unnecessary or complicated.

Combined QSAR studies of inhibitor properties of O-phosphorylated oximes toward serine esterases involved in neurotoxicity, drug metabolism and Alzheimer's disease

Oxime reactivation of serine esterases (EOHs) inhibited by organophosphorus (OP) compounds can produce O-phosphorylated oximes (POXs). Such oxime derivatives are of interest, because some of them can have greater anti-EOH potencies than the OP inhibitors from which they were derived. Accordingly, inhibitor properties of 58 POXs against four EOHs, along with pair-wise selectivities between them, have been analysed using different QSAR approaches. EOHs (with their abbreviations and consequences of inhibition in parentheses) comprised acetylcholinesterase (AChE: acute neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: delayed neurotoxicity). QSAR techniques encompassed linear regression and backpropagation neural networks in conjunction with fragmental descriptors containing labelled atoms, Molecular Field Topology Analysis (MFTA), Comparative Molecular Similarity Index Analysis (CoMSIA), and molecular modelling. All methods provided mostly consistent and complementary information, and they revealed structural features controlling the ‘esterase profiles’, i.e. patterns of anti-EOH activities and selectivities of the compounds of interest. In addition, MFTA models were used to design a library of compounds having a cognition-enhancement esterase profile suitable for potential application to the treatment of Alzheimers disease.

Progress in visual representations of chemical space.

Introduction: The concept of ‘chemical space’ reveals itself in two forms: the discrete set of all possible molecules, and multi-dimensional descriptor space encompassing all the possible molecules. Approaches based on this concept are widely used for the analysis and enumeration of compound databases, library design, and structure–activity relationships (SAR) and landscape studies. Visual representations of chemical space differ in their applicability domains and features and require expert knowledge for choosing the right tool for a particular problem. Areas covered: In this review, the authors present recent advances in visualization of the chemical space in the framework of current general understanding of this topic. Attention is given to such methods as van Krevelen diagrams, descriptor plots, principal components analysis (PCA), self-organizing maps (SOM), generative topographic mapping (GTM), graph and network-based approaches. Notable application examples are provided. Expert opinion: With the growth of computational power, representations of large datasets are becoming more and more common instruments in the toolboxes of chemoinformaticians. Every scientist in the field can find the method of choice for a particular task. However, there is no universal reference representation of the chemical space currently available and expert knowledge is required.

Chapter 5:Molecular Field Topology Analysis in Drug Design and Virtual Screening

During the search for effective drugs and other bioactive compounds, attention is usually focused on specific activity stemming from the “receptor-like” interactions of small organic ligand molecules with a well-defined biological target (enzyme, receptor, etc.).1 The nature and strength of such int...

Molecular design of O -phosphorylated oximes—Selective inhibitors of butyrylcholinesterase

Anticholinesterase compounds, including organophosphorus inhibitors (OPIs), are used to treat glaucoma, schistosomiasis, Alzheimer’s disease, myasthenia gravis, and other diseases. These compounds arealso widely used in agriculture as insecticides and inindustry [1]. The varied use of such compounds isbased on their common mechanism of action, which isassociated with the inhibition of acetylcholinesterase(AChE, EC 3.1.1.7), the biological role of which is thehydrolysis of the key neurotransmitter acetylcholine.In the treatment of Alzheimer’s disease (AD) underconditions of deficiency of central acetylcholine andreduced cholinergic transmission, the inhibition ofAChE in the brain provides cognition enhancement,which, however, may be accompanied by manifestations of acute toxicity and other side effects associatedwith inhibition of peripheral AChE [2].Many OPIs interact in the body with otheresterases. These interactions may lead to differentpharmacological and toxicological effects. For example, the neuropathy target esterase (NTE, EC 3.1.1.5),which normally catalyzes deacylation of phosphatidylcholine of cell membranes [3], is an “antitarget”responsible for the development of organophosphateinduced delayed neurotoxicity (OPIDN). This phenomenon is due to the fact that its inhibition and subsequent rapid “aging” initiates distal degeneration ofsensory and motor axons in the peripheral nervous system and/or spinal cord, causing paralysis [1]. This disease is characterized by a latent period of up to severalweeks; specific drugs for its treatment are still notknown. Thus, the possibility of initiation of delayedneurotoxicity is an important risk factor in industrialand medical applications of OPIs.Other serine esterases, such as butyrylcholinesterase (BChE, EC 3.1.1.8) and carboxylesterase (CaE,EC 3.1.1.1), function as stoichiometric scavengers,providing protection against the toxic effect of anticholinesterase agents [4]. BChE and CaE of bloodplasma and liver are also in volved in the metabolism ofmany drugs containing ester groups, significantlyaffecting their pharmacokinetics.Recent studies have shown that BChE is alsoinvolved in cholinergic transmission and is able tocompensate for some functions of AChE, optimizingthe cholinergic neurotransmission by hydrolysis ofacetylcholine under conditions when AChE is, forsome reason, unable to perform this function(for example, in severe forms of AD, when the activityof AChE is significantly reduced). It was found thatselective inhibitors of BChE increase the level of acetylcholine in the brain and provide cognition enhancement in rodents, having no side effects of classicalinhibitors of AChE. In this regard, the development ofselective inhibitors of BChE is a new strategy toimprove the quality of life of patients with AD, especially in severe cases, when the activity of AChE in thebrain is depleted along with a decrease in the level ofacetylcholine, whereas the activity of BChE isincreased [2].Within the considered scheme of interaction withthe four serine esterases, the esterase profile of aninhibitor can be described by four activity values(the inhibitory activity with respect to AChE

Synthesis and biological evaluation of novel 5-hydroxylaminoisoxazole derivatives as lipoxygenase inhibitors and metabolism enhancing agents

A versatile synthesis of novel 5-hydroxylaminoisoxazoles bearing adamantane moieties has been accomplished using the heterocyclization reactions of readily available unsaturated esters by the treatment with tetranitromethane in the presence of triethylamine and subsequent reduction of resulting 5-nitroisoxazoles by SnCl2 with the participation of THF. A number of obtained isoxazole derivatives were evaluated for their antioxidative activity, inhibition of lipoxygenases and impact on the rat liver mitochondria. The majority of tested compounds demonstrated moderate antiradical activity in DPPH test (up to EC50 16μM). The same compounds strongly inhibited soybean lipoxygenase (up to IC50 0.4μM) and Fe(2+)- and Fe(3+)-induced lipid peroxidation (LP) of rat brain cortex homogenate (up to IC50 0.3μM). All tested isoxazole derivatives promoted the phosphorylating respiratory activity simultaneously with maximal stimulated respiratory activity of mitochondria and do not reveal any toxicity towards the primary culture of rat cortex neurons.

Molecular design of N , N -disubstituted 2-aminothiazolines as selective carboxylesterase inhibitors

Selective carboxylesterase inhibitors are employed as modulators of hydrolytic metabolism of ester or amide-containing drugs. Using the Molecular Field Topology Analysis (MFTA), the models for the relationships between the structures and inhibitory activities of 5-halomethyl-2-aminothiazolines against acetylcholinesterase, butyrylcholinesterase, and carboxylesterase were built, the molecular design was performed, and a focused library of potentially active and selective carboxylesterase inhibitors was proposed.

Prediction of human intestinal absorption of drug compounds

Absorption in the small intestine is one of the key processes determining the drug bioavailability upon oral administration. Using fragmental descriptors and artificial neural networks, a predictive model for the relationship between the structure and human intestinal absorption of organic compounds was built and the structural factors affecting the ease of absorption were analyzed. This model is superior in the prediction accuracy and the applicability domain to other known models and can be used in the optimization of pharmacokinetic parameters during drug design.