Fluoroquinolone Derivatives in the Treatment of Infection.

Tuberculosis (TB) is currently one of the leading causes of death due to infective agents, and the growing rate of multidrug-resistant tuberculosis (MDR TB) cases poses an emergent public health threat. Fluoroquinolones are commonly used in the treatment of both MDR TB and drug-sensitive tuberculosis patients who are intolerant to first-line antitubercular agents. Unfortunately, these drugs have mild side effects, relevant to the prolonged treatment regimens and diminished bioavailability due to binding of metal ions.

Benzoic Acid Derivatives as Prodrugs for the Treatment of Tuberculosis.

One interesting approach to fight tuberculosis is the use of prodrugs that often have shown improved biological activities over drugs with poor absorption or difficulty to cross membranes. Previous studies demonstrate that weak acids such as benzoic acid, present antimycobacterial activity. Moreover, esters of those acids revealed to be a viable alternative since they may diffuse more easily through the cell membranes.

Activation of benzoate model prodrugs by mycobacteria. Comparison with mammalian plasma and liver hydrolysis.

Due to difficulties in drug penetration in M. tuberculosis, a prodrug approach based on mycobacterial activation appears as a promising strategy to increase the delivery of antitubercular drugs to the target microorganisms. Esters have been successful used by us and others to deliver drugs to mycobacteria, however because very little is known about the metabolic hydrolysis of esters by mycobacteria in connection with prodrug activation, we decided to study the process further.

FAME 3: Predicting the Sites of Metabolism in Synthetic Compounds and Natural Products for Phase 1 and Phase 2 Metabolic Enzymes.

In this work we present the third generation of FAst MEtabolizer (FAME 3), a collection of extra trees classifiers for the prediction of sites of metabolism (SoMs) in small molecules such as drugs, druglike compounds, natural products, agrochemicals, and cosmetics. FAME 3 was derived from the MetaQSAR database ( Pedretti et al. 2018 , 61 , 1019 ), a recently published data resource on xenobiotic metabolism that contains more than 2100 substrates annotated with more than 6300 experimentally confirmed SoMs related to redox reactions, hydrolysis and other nonredox reactions, and conjugation reactions.

Prediction of UGT-mediated Metabolism Using the Manually Curated MetaQSAR Database.

Even though glucuronidations are the most frequent metabolic reactions of conjugation, both in quantitative and qualitative terms, they have rather seldom been investigated using computational approaches. To fill this gap, we have used the manually collected MetaQSAR metabolic reaction database to generate two models for the prediction of UGT-mediated metabolism, both based on molecular descriptors and implementing the Random Forest algorithm. The first model predicts the occurrence of the reaction and was internally validated with a Matthew correlation coefficient (MCC) of 0.

Prediction of the Formation of Reactive Metabolites by A Novel Classifier Approach Based on Enrichment Factor Optimization (EFO) as Implemented in the VEGA Program.

The study is aimed at developing linear classifiers to predict the capacity of a given substrate to yield reactive metabolites. While most of the hitherto reported predictive models are based on the occurrence of known structural alerts (e.g.

Emerging Chemodiversity and Stereoisomerism in Acyclic Mono- and Dichloroalkanes.

The objective of this pen-and-paper study is to monitor the growth of structural complexity as a function of the number of heavy atoms. This is done here using simple chloroalkanes, the indices of structural complexity being the number of regioisomers and mainly stereoisomeric features. Following a previous work dealing with acyclic alkanes, the present study focuses on all acyclic monochloroalkanes from four heavy atoms (four regioisomers) to 10 heavy atoms (2 to 211 regioisomers, respectively).

Approaching Pharmacological Space: Events and Components.

With a view to introducing the concept of pharmacological space and its potential applications in investigating and predicting the toxic mechanisms of xenobiotics, this opening chapter describes the logical relations between conformational behavior, physicochemical properties and binding spaces, which are seen as the three key elements composing the pharmacological space. While the concept of conformational space is routinely used to encode molecular flexibility, the concepts of property spaces and, particularly, of binding spaces are more innovative. Indeed, their descriptors can find fruitful applications (a) in describing the dynamic adaptability a given ligand experiences when inserted into a specific environment, and (b) in parameterizing the flexibility a ligand retains when bound to a biological target.

MetaQSAR: An Integrated Database Engine to Manage and Analyze Metabolic Data.

The study describes the MetaQSAR tool, a new database engine specifically tailored to collect and analyze metabolic data. This is a plug-in embedded in the VEGA suite of programs (freely downloadable at www.vegazz.

Emergent chemodiversity: The case of stereoisomerism in acyclic alkanes.

The objective of this pen-and-paper study is to witness the emergence of stereoisomeric properties when comparing lower to higher families of homologs. Specifically, the study compares all acyclic hexanes (five constitutional isomers, a.k.

Binding Space Concept: A New Approach To Enhance the Reliability of Docking Scores and Its Application to Predicting Butyrylcholinesterase Hydrolytic Activity.

Docking simulations are very popular approaches able to assess the capacity of a given ligand to interact with a target. Docking simulations are usually focused on a single best complex even though many studies showed that ligands retain a significant mobility within a binding pocket by assuming different binding modes all of which may contribute to the monitored ligand affinity. The present study describes an innovative concept, the binding space, which allows an exploration of the ligand mobility within the binding pocket by simultaneously considering several ligand poses as generated by docking simulations.

Mechanisms and pharmaceutical consequences of processes of stereoisomerisation - A didactic excursion.

This writing proposes an overview of chemical processes of isomerisation involving conformations and configurational isomers. Molecular structure is depicted as consisting in A) core features; and B) fluctuating properties. To avoid confusion and misuses in terminology, attention is paid to IUPAC recommendations and definitions, beginning with a focus on conformers versus conformations.

Esters of Pyrazinoic Acid Are Active against Pyrazinamide-Resistant Strains of Mycobacterium tuberculosis and Other Naturally Resistant Mycobacteria In Vitro and Ex Vivo within Macrophages.

Pyrazinamide (PZA) is active against major Mycobacterium tuberculosis species (M. tuberculosis, M. africanum, and M.

Predicting drug metabolism: experiment and/or computation?

Drug metabolism can produce metabolites with physicochemical and pharmacological properties that differ substantially from those of the parent drug, and consequently has important implications for both drug safety and efficacy. To reduce the risk of costly clinical-stage attrition due to the metabolic characteristics of drug candidates, there is a need for efficient and reliable ways to predict drug metabolism in vitro, in silico and in vivo. In this Perspective, we provide an overview of the state of the art of experimental and computational approaches for investigating drug metabolism.

Types of stereoselectivity in drug metabolism: a heuristic approach.

Stereochemical factors are known to play a significant role in the metabolism of drugs and other xenobiotics. Following Prelog's lead, types of metabolic stereoselectivity can be categorized as (i) substrate stereoselectivity (the differential metabolism of two or more stereoisomeric substrates) and (ii) product stereoselectivity (the differential formation of two or more stereoisomeric metabolites from a single substrate). Combinations of the two categories exist as (iii) substrate-product stereoselectivities, meaning that product stereoselectivity itself is substrate stereoselective.

Passive lipoidal diffusion and carrier-mediated cell uptake are both important mechanisms of membrane permeation in drug disposition.

Recently, it has been proposed that drug permeation is essentially carrier-mediated only and that passive lipoidal diffusion is negligible. This opposes the prevailing hypothesis of drug permeation through biological membranes, which integrates the contribution of multiple permeation mechanisms, including both carrier-mediated and passive lipoidal diffusion, depending on the compound's properties, membrane properties, and solution properties. The prevailing hypothesis of drug permeation continues to be successful for application and prediction in drug development.

Quantitative monitoring of tamoxifen in human plasma extended to 40 metabolites using liquid-chromatography high-resolution mass spectrometry: new investigation capabilities for clinical pharmacology.

Liquid-chromatography (LC) high-resolution (HR) mass spectrometry (MS) analysis can record HR full scans, a technique of detection that shows comparable selectivity and sensitivity to ion transitions (SRM) performed with triple-quadrupole (TQ)-MS but that allows de facto determination of "all" ions including drug metabolites. This could be of potential utility in in vivo drug metabolism and pharmacovigilance studies in order to have a more comprehensive insight in drug biotransformation profile differences in patients. This simultaneous quantitative and qualitative (Quan/Qual) approach has been tested with 20 patients chronically treated with tamoxifen (TAM).

Exploring the space of histidine containing dipeptides in search of novel efficient RCS sequestering agents.

The study reports a set of forty proteinogenic histidine-containing dipeptides as potential carbonyl quenchers. The peptides were chosen to cover as exhaustively as possible the accessible chemical space, and their quenching activities toward 4-hydroxy-2-nonenal (HNE) and pyridoxal were evaluated by HPLC analyses. The peptides were capped at the C-terminus as methyl esters or amides to favor their resistance to proteolysis and diastereoisomeric pairs were considered to reveal the influence of configuration on quenching.

Simulations in evolution. III. Randomness as a generator of opportunities.

In Neo-Darwinism, variation and natural selection are the two evolutionary mechanisms which propel biological evolution. Our previous reports presented a histogram model to simulate the evolution of populations of individuals classified into bins according to an unspecified, quantifiable phenotypic character, and whose number in each bin changed generation after generation under the influence of fitness, while the total population was maintained constant. The histogram model also allowed Shannon entropy (SE) to be monitored continuously as the information content of the total population decreased or increased.

Lack of enantioselectivity in the SULT1A3-catalyzed sulfoconjugation of normetanephrine enantiomers: an in vitro and computational study.

(1R)-Normetanephrine is the natural stereoisomeric substrate for sulfotransferase 1A3 (SULT1A3)-catalyzed sulfonation. Nothing appears known on the enantioselectivity of the reaction despite its potential significance in the metabolism of adrenergic amines and in clinical biochemistry. We confronted the kinetic parameters of the sulfoconjugation of synthetic (1R)-normetanephrine and (1S)-normetanephrine by recombinant human SULT1A3 to a docking model of each normetanephrine enantiomer with SULT1A3 and the 3'-phosphoadenosine-5'-phosphosulfate cofactor on the basis of molecular modeling and molecular dynamics simulations of the stability of the complexes.

Screening of the inhibitory effect of xenobiotics on alcohol metabolism using S9 rat liver fractions.

The purpose of this work was to develop and optimize a simple and suitable method to detect the potential inhibitory effect of drugs and medicines on alcohol dehydrogenase (ADH) activity in order to evaluate the possible interactions between medicines and alcohol metabolism. Commonly used medicines that are often involved in court litigations related with driving under the influence of alcohol were selected. Alprazolam, flunitrazepam and tramadol were tested as drugs with no known effect on ADH activity.

Predicting the physicochemical profile of diastereoisomeric histidine-containing dipeptides by property space analysis.

Objectives: This study aimed at measuring the lipophilicity and ionization constants of diastereoisomeric dipeptides, interpreting them in terms of conformational behavior, and developing statistical models to predict them.

Methods: A series of 20 dipeptides of general structure NH(2)-L-X-(L or D)-His-OMe was designed and synthetized. Their experimental ionization constants (pK(1), pK(2) and pK(3)) and lipophilicity parameters (log P(N) and log D(7.

Reactions and enzymes in the metabolism of drugs and other xenobiotics.

In this article, we offer an overview of the compared quantitative importance of biotransformation reactions in the metabolism of drugs and other xenobiotics, based on a meta-analysis of current research interests. Also, we assess the relative significance the enzyme (super)families or categories catalysing these reactions. We put the facts unveiled by the analysis into a drug discovery context and draw some implications.