Identification in silico and in vitro of novel trypanosomicidal drug-like compounds

Atom‐based bilinear indices and linear discriminant analysis are used to discover novel trypanosomicidal compounds. The obtained linear discriminant analysis‐based quantitative structure–activity relationship models, using non‐stochastic and stochastic indices, provide accuracies of 89.02% (85.11%) and 89.60% (88.30%) of the chemicals in the training (test) sets, respectively. Later, both models were applied to the virtual screening of 18 in‐house synthesized compounds to find new pro‐lead antitrypanosomal agents. The in vitro antitrypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Predictions agree with experimental results to a great extent (16/18) of the chemicals. Sixteen compounds show more than 70% of epimastigote inhibition at a concentration 100 μg/mL. In addition, three compounds ( CRIS 112 , CRIS 140 and CRIS 147 ) present more than 70% of epimastigote inhibition at a concentration of 10 μg/mL (79.95%, 73.97% and 78.13%, respectively) with low values of cytotoxicity (19.7%, 7.44% and 20.63%, correspondingly).Taking into account all these results, we could say that these three compounds could be optimized in forthcoming works. Even though none of them resulted more active than nifurtimox, the current results constitute a step forward in the search for efficient ways to discover new lead antitrypanosomals.     

Three-dimensional structure generators of drug-like compounds: DG-AMMOS,an open-source package

Introduction: Drug discovery is a time consuming and costly process. Thus, a trend towards the use of in silico approaches such as structure- and ligand-based virtual screening methods to speed up the process has gained significant momentum in recent years. Most of these in silico applications require a good quality 3D structure of the small drug-like molecules as input.

Areas covered: This article reviews the algorithm and validation of the open-source software DG-AMMOS, a tool that generates the 3D conformation of small molecules using distance geometry construction and molecular mechanics optimization comparing its performance with some related free and commercial packages.

Expert opinion: The number of chemo/bioinformatics free and/or open-source tools assisting drug discovery projects is increasing, and many successful contributions making use of these computer programs have been reported. DG-AMMOS is an efficient 3D structure generator engine that provides fast and reliable generation of 3D structures and contributes to the preparation of a compound collection. DG-AMMOS can still be improved and an increased speed and user-friendly interface in addition to the implementation of workflow engines will increase its effectiveness.     

Three-dimensional structure generators of drug-like compounds: DG-AMMOS, an open-source package

Introduction: Drug discovery is a time consuming and costly process. Thus, a trend towards the use of in silico approaches such as structure- and ligand-based virtual screening methods to speed up the process has gained significant momentum in recent years. Most of these in silico applications require a good quality 3D structure of the small drug-like molecules as input. Areas covered: This article reviews the algorithm and validation of the open-source software DG-AMMOS, a tool that generates the 3D conformation of small molecules using distance geometry construction and molecular mechanics optimization comparing its performance with some related free and commercial packages. Expert opinion: The number of chemo/bioinformatics free and/or open-source tools assisting drug discovery projects is increasing, and many successful contributions making use of these computer programs have been reported. DG-AMMOS is an efficient 3D structure generator engine that provides fast and reliable generation of 3D structures and contributes to the preparation of a compound collection. DG-AMMOS can still be improved and an increased speed and user-friendly interface in addition to the implementation of workflow engines will increase its effectiveness.     

A review of QSAR studies to discover new drug-like compounds actives against leishmaniasis and trypanosomiasis

The neglected tropical diseases (NTDs) affect more than one billion people (one-sixth of the world's population) and occur primarily in undeveloped countries in sub-Saharan Africa, Asia, and Latin America. Available drugs for these diseases are decades old and present an important number of limitations, especially high toxicity and, more recently, the emergence of drug resistance. In the last decade several Quantitative Structure-Activity Relationship (QSAR) studies have been developed in order to identify new organic compounds with activity against the parasites responsible for these diseases, which are reviewed in this paper. The topics summarized in this work are: 1) QSAR studies to identify new organic compounds actives against Chaga's disease; 2) Development of QSAR studies to discover new antileishmanial drusg; 3) Computational studies to identify new drug-like compounds against human African trypanosomiasis. Each topic include the general characteristics, epidemiology and chemotherapy of the disease as well as the main QSAR approaches to discovery/identification of new actives compounds for the corresponding neglected disease. The last section is devoted to a new approach know as multi-target QSAR models developed for antiparasitic drugs specifically those actives against trypanosomatid parasites. At present, as a result of these QSAR studies several promising compounds, active against these parasites, are been indentify. However, more efforts will be required in the future to develop more selective (specific) useful drugs.     

The identification and biochemical characterization of drug-like compounds that inhibit botulinum neurotoxin serotype A endopeptidase activity

A robust, high-throughput, two-tiered assay for screening small molecule inhibitors against botulinum neurotoxin serotype A was developed and employed to screen 16,544 compounds. Thirty-four compounds were identified as potent hits employing the first-tier assay. Subsequently, nine were confirmed as actives by our second-tier confirmatory assay. Of these, one displayed potent inhibitory efficacy, possessing an IC₅₀ = 16 μM (±1.6 μM) in our in vitro assay. This inhibitor (0831-1035) is highly water-soluble, and possesses an IC₅₀ = 47 μM (±7.0 μM) in our primary cell culture assay (with virtually no cytotoxicity up to 500 μM), suggesting that this inhibitor is a good candidate for further development as a therapeutic countermeasure to treat botulism resulting from botulinum neurotoxin serotype A intoxication. An enzyme kinetics study indicated that this inhibitor exhibits mixed non-competitive inhibition, with a K_I = 9 μM.     

The general practitioner's role in AOD issues: overcoming individual,professional and systemic barriers

General practitioners (GPs) and increasingly other medical practitioners are well placed to address alcohol and other drug (AOD) problems. Their involvement in this area of care, however, is assessed to be less than optimal. There is, however, a growing body of evidence for the potential efficacy of medical practitioner intervention at the primary care, emergency department and in-patient level. There is also considerably expanded scope to operate from an evidence-based perspective. However, key questions arise regarding what constitutes best practice in the translation of the growing AOD knowledge base into clinical practice behaviours. This paper explores possible contributory factors to the low level of engagement with AOD issues by GPs and examines a wide range of individual, structural and systemic issues that may be amenable to change. Strategies for the dissemination of research findings, changing professional practice behaviour and introducing sustainable structural reforms are also addressed.     

In silico approaches to prediction of aqueous and DMSO solubility of drug-like compounds: trends, problems and solutions

The solubility of drugs and drug-like compounds has been the subject of extensive studies aimed at finding a way to predict solubility from molecular structure. The aqueous solubility of a drug is an important factor that influences its absorption, distribution and elimination in the body. Poor aqueous solubility often causes a drug to appear inactive and may cause other biological problems. Compound solubility in DMSO represents another serious problem in early stages of drug discovery. An appreciation of the factors affecting a compound's DMSO solubility could help in predicting the storage conditions and appropriateness of compounds for primary bioscreening programs. In silico procedures for estimation of water and DMSO solubility represent extremely useful tools for the drug discovery practitioners. In this review, we provide a critical discussion of in silico models for the prediction of DMSO and water solubility of drug-like compounds used for virtual screening. We describe the main tendencies in the field, "booming" approaches and unsolved problems. A critical analysis of the accuracy and applicability of methods is provided.     

Computer-based de novo design of drug-like molecules

Ever since the first automated de novo design techniques were conceived only 15 years ago, the computer-based design of hit and lead structure candidates has emerged as a complementary approach to high-throughput screening. Although many challenges remain, de novo design supports drug discovery projects by generating novel pharmaceutically active agents with desired properties in a cost- and time-efficient manner. In this review, we outline the various design concepts and highlight current developments in computer-based de novo design.     

Aspartate and glutamate mimetic structures in biologically active compounds

Glutamate and aspartate are frequently recognized as key structural elements for the biological activity of natural peptides and synthetic compounds. The acidic side-chain functionality of both the amino acids provides the basis for the ionic interaction and subsequent molecular recognition by specific receptor sites that results in the regulation of physiological or pathophysiological processes in the organism. In the development of new biologically active compounds that possess the ability to modulate these processes, compounds offering the same type of interactions are being designed. Thus, using a peptidomimetic design approach, glutamate and aspartate mimetics are incorporated into the structure of final biologically active compounds. This review covers different bioisosteric replacements of carboxylic acid alone, as well as mimetics of the whole amino acid structure. Amino acid analogs presented include those with different distances between anionic moieties, and analogs with additional functional groups that result in conformational restriction or alternative interaction sites. The article also provides an overview of different cyclic structures, including various cycloalkane, bicyclic and heterocyclic analogs, that lead to conformational restriction. Higher di- and tripeptide mimetics in which carboxylic acid functionality is incorporated into larger molecules are also reviewed. In addition to the mimetic structures presented, emphasis in this article is placed on their steric and electronic properties. These mimetics constitute a useful pool of fragments in the design of new biologically active compounds, particularly in the field of RGD mimetics and excitatory amino acid agonists and antagonists.     

Catalysis in aqueous media for the synthesis of drug-like molecules

The design of straightforward and practical chemical syntheses that satisfy economic and ecological constraints is a major challenge in R&D. Ideally, a sustainable chemical synthesis should be safe, environmentally benign, reasonable in terms of cost, and careful in the use of resources and energy. The capability to develop synthetic strategies that meet these criteria is a priority in the manufacture of fine chemicals and pharmaceuticals, considering that the health and welfare of society increasingly depend on such industries. Among the various objectives to be pursued in sustainable manufacturing, this review focuses on two main goals: (i) the minimization of waste; and (ii) the replacement of toxic and volatile organic solvents with alternative, safer solvents - specifically water. In this context, the development of methods for catalysis in alternative reaction media is recognized as one of the most important approaches in modern chemical production.     

The influence of drug-like concepts on decision-making in medicinal chemistry

The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity--the most important drug-like physical property--include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.     

Economic issues with follow-on protein products

The economic effects of the possible introduction of 'follow-on' protein products have been the subject of recent debate. Here, we aim to explore the economic issues surrounding this debate using three measures: total sales, product complexity and patent expiry. Our analysis shows that the sales of therapeutic protein products are concentrated in a relatively small number of branded products, which may be the most attractive targets for follow-on development. For the years 2013-2015, we estimate that products representing US$20 billion in annual sales--approximately half of all sales in 2006--can be expected to lose patent protection.     

Residue contacts in protein structures and implications for protein folding

The preferential association of amino acid side groups with specific side chain atoms are examined in 44 known protein structures. The resulting association potentials among residue side groups are used to detect structural homology in proteins displaying little or no homology in their primary sequences. Suggestions are also made regarding the nature of the protein folding process. They are based on statistical observations that delineate the extent of short and long range interactions and that display side group bias in association with other side chain atoms on their N-terminal side.     

Patenting 3D protein structures

The sequencing of entire genomes of living organisms has resulted in new potential inventions in the field of bioinformatics. Such sequence information will revolutionise the field of structural genomics by allowing for the identification of biological molecules, such as DNA, RNA and proteins, involved in disease. The information may also lead to the identification of protein families and mutations in proteins that are potentially related to disease and the determination of the 3D structure of such protein families and mutated proteins. Such 3D structural information has great therapeutic potential. It is useful, inter alia, for understanding the mechanism of action of proteins with respect to disease that, in turn, can lead to new therapies. In addition, the information is useful in rational drug design, for example, the 3D structure of mutated proteins known to have lost a particular desired activity associated with the wild type protein can lead to the identification of a small molecule capable of re-establishing wild type activity; alternatively, it may be desirable to design an inhibitory molecule that binds to the mutated protein and inhibits an undesirable activity associated with the mutated protein. Although such information has great therapeutic potential, there are few issued patents relating to the 3D structural information of proteins. However, under appropriate circumstances, it should be possible to obtain commercially significant patent protection relating to such structure information.     

Strategic approaches for overcoming peptide and protein instability within biodegradable nano- and microparticles.

This paper reviews the major factors that are closely involved in peptide and protein degradation during the preparation of biodegradable nano- and microparticles. The various means usually employed for overcoming these obstacles are described, in order to bring to the fore the strategies for protein stabilization. Both processing and formulation parameters can be modified and are distinctly considered from a strategic point of view. We describe how partial or full protein stability retention within the carriers and during drug release might be achieved by individual or combined optimized strategies. Additionally, problems commonly encountered during protein quantification, stability determination and release are briefly reviewed. Artefacts that might occur during sampling and analytical procedures and which might hinder critical interpretation of results are discussed.