Solvate Suite: A Command-Line Interface for Molecular Simulations and Multiscale Microsolvation Modeling.

In this work, we introduce the Solvate Suite, a comprehensive and modular command-line interface designed for molecular simulation and microsolvation modeling. The suite interfaces with widely used scientific software, streamlining computational experiments for liquid systems through the automated creation of simulation boxes and topology with adjustable simulation parameters. Furthermore, it has features for graphical and statistical analysis of simulated properties and extraction of trajectory configurations with various filters. Additionally, it introduces innovative strategies for microsolvation modeling with a multiscale approach, employing equilibrated dynamics to identify favorable solute-solvent interactions and enabling full cluster optimization for free-energy calculations without imaginary frequency contamination.

Anterior thalamic NMDA-induced damage impairs extrapolation relying on serial stimulus patterns, in rats.

Extrapolation of serial stimulus patterns seems to depend upon identification and application of patterns relating sequences of stimuli stored in memory, thus allowing prediction of pending events never experienced before. There have been proposals that such a "generator of predictions system" would include the subiculum, mammillary bodies, anteroventral thalamus and cingulate cortex (e.g., Gray, 1982). The anteroventral thalamus (AVT) seems to be in a strategic position, both hodologically and experimentally, to allow testing of this hypothesis. This study investigated the effect of NMDA-induced damage to the anteroventral thalamus [part of the anterodorsal (AD) thalamus was also damaged in some animals], following stereotaxic minute topic microinjections, on the ability of male Wistar rats to extrapolate relying on serial stimulus patterns. Corresponding sham-operated controls received phosphate-saline buffer microinjections at the same stereotaxic coordinates. The subjects were trained to run through a straight alleyway along 31 sessions, one session per day, to get rewarded. Each session included four successive trials. Subjects exposed to the monotonic serial pattern received 14, 7, 3, 1 sunflower seeds along trials. Subjects exposed to the non-monotonic serial pattern received 14, 3, 7, 1 sunflower seeds. On the 32nd testing session, a fifth trial, never experienced before, was included immediately after the fourth trial. Sham-operated control subjects exposed to the monotonic serial pattern were expected to exhibit longer running times, since the content of their prediction in the fifth trial should be "less than 1 sunflower seeds". In contrast, control subjects exposed to the non-monotonic serial pattern were expected to exhibit shorter running times, since the content of their prediction would be "more than 1 sunflower seeds". Confirming these predictions, control subjects exposed to the monotonic serial pattern exhibited longer running times as compared to both, their own running times in previous trials within the same session and control subjects exposed to the non-monotonic schedule, thus indicating the occurrence of extrapolation. In contrast, AVT/AD lesioned subjects exposed to the monotonic schedule did not exhibit this increase in running times on the fifth trial, indicating lack of extrapolation. These results indicate that extrapolation relying on serial stimulus patterns is disrupted following extensive NMDA-induced damage to AVT and part of the AD. This represents the first consistent demonstration that the anterior thalamic nuclei are required for extrapolation of serial stimulus patterns and generation of predictions.

A comparative study of warheads for design of cysteine protease inhibitors.

The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the α methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude.

Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus.

Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens, and the results were made publicly available through the Open Source Antibiotics (OSA) consortium (https://github.com/opensourceantibiotics). Of the 18 compounds tested (at 32 µg/mL), 15 showed >90% growth inhibition activity against methicillin-resistant Staphylococcus aureus (MRSA) alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized and tested against MRSA, and their structure-activity relationships were identified. While potent, these compounds have moderate to high intrinsic clearance and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency, good solubility, and reduced intrinsic clearance in rat hepatocytes. We have progressed toward the knowledge of the molecular target of these phenotypically active compounds, with proteomic techniques suggesting TGFBR1 is potentially involved in the mechanism of action. Further development of these compounds toward antimicrobial medicines is available to anyone under the licensing terms of the project.

Estuarine Aquacultures at the Crossroads of Animal Production and Antibacterial Resistance: A Metagenomic Approach to the Resistome.

It is recognized that the spread of antibiotic resistance (AR) genes among aquatic environments, including aquaculture and the human environment, can have detrimental effects on human and animal health and the ecosystem. Thus, when transmitted to the human microbiome or pathogens, resistance genes risk human health by compromising the eventual treatment of infections with antibiotic therapy. This study aimed to define the resistance profile of aquaculture farms and their potential risk for spreading. Twenty-four sediments from oyster and gilthead sea bream aquaculture farms located in three Portuguese river estuaries (17 sediments from Sado, 4 from Aveiro, and 3 from Lima) were studied by comparative metagenomic analysis. The computation of the diversity of genes conferring resistance per antibiotic class revealed a significant increase in aminoglycosides, beta-lactams, disinfectants, quinolones, and tetracyclines counts. In all geographic locations under study, the most diverse AR genes confer resistance to the macrolides, tetracyclines and oxazolidinones classes, all of which are medically important for human and animal therapies, as well as resistance to disinfectants. The diversity of mobile genetic elements correlated with the number of AR genes such as tetracyclines, suggesting that AR could be easily mobilized among bacterial genomes and microbiomes.

Development of Novel Isoindolone-Based Compounds against Trypanosoma brucei rhodesiense.

This study identified the isoindolone ring as a scaffold for novel agents against Trypanosoma brucei rhodesiense and explored the structure-activity relationships of various aromatic ring substitutions. The compounds were evaluated in an integrated in vitro screen. Eight compounds exhibited selective activity against T. b. rhodesiense (IC50 <2.2 µm) with no detectable side activity against T. cruzi and Leishmania infantum. Compound 20 showed low nanomolar potency against T. b. rhodesiense (IC50 =40 nm) and no toxicity against MRC-5 and PMM cell lines and may be regarded as a new lead template for agents against T. b. rhodesiense. The isoindolone-based compounds have the potential to progress into lead optimization in view of their highly selective in vitro potency, absence of cytotoxicity and acceptable metabolic stability. However, the solubility of the compounds represents a limiting factor that should be addressed to improve the physicochemical properties that are required to proceed further in the development of in vivo-active derivatives.

Synthesis and Structure-Activity Relationships of Imidazopyridine/Pyrimidine- and Furopyridine-Based Anti-infective Agents against Trypanosomiases.

Neglected tropical diseases remain among the most critical public health concerns in Africa and South America. The drug treatments for these diseases are limited, which invariably leads to fatal cases. Hence, there is an urgent need for new antitrypanosomal drugs. To address this issue, a large number of diverse heterocyclic compounds were prepared. Straightforward synthetic approaches tolerated pre-functionalized structures, giving rise to a structurally diverse set of analogs. We report on a set of 57 heterocyclic compounds with selective activity potential against kinetoplastid parasites. In general, 29 and 19 compounds of the total set could be defined as active against Trypanosoma cruzi and T. brucei brucei, respectively (antitrypanosomal activities <10 µM). The present work discusses the structure-activity relationships of new fused-ring scaffolds based on imidazopyridine/pyrimidine and furopyridine cores. This library of compounds shows significant potential for anti-trypanosomiases drug discovery.

Development of the First Potential Nonpeptidic Positron Emission Tomography Tracer for the Imaging of CCR2 Receptors.

Herein we report the design and synthesis of a series of highly selective CCR2 antagonists as 18 F-labeled PET tracers. The derivatives were evaluated extensively for their off-target profile at 48 different targets. The most potent and selective candidate was applied in vivo in a biodistribution study, demonstrating a promising profile for further preclinical development. This compound represents the first potential nonpeptidic PET tracer for the imaging of CCR2 receptors.

On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors.

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. Hence, peptidomimetic cruzipain inhibitors having a reactive group (known as warhead) are subject to continuous studies to discover novel antichagasic compounds. Here, we evaluated how different warheads for a set of structurally similar related compounds could inhibit the activity of cruzipain and, ultimately, their trypanocidal effect. We first investigated in silico the intrinsic reactivity of these compounds by applying the Fukui index to correlate it with the enzymatic affinity. Then, we evaluated their potency against T. cruzi (Y and Tulahuen strains), which revealed the reversible cruzain inhibitor Neq0656 as a better trypanocidal agent (ECY.strain 50 = 0.1 µM; SI = 58.4) than the current drug benznidazole (ECY.strain 50 = 5.1 µM; SI > 19.6). We also measured the half-life time by HPLC analysis of three lead compounds in the presence of glutathione and cysteine to experimentally assess their intrinsic reactivity. Results clearly illustrated the reactivity trend for the warheads (azanitrile > aldehyde > nitrile), where the aldehyde displayed an intermediate intrinsic reactivity. Therefore, the aldehyde bearing peptidomimetic compounds should be subject for in-depth evaluation in the drug discovery process.

New Class of Antitrypanosomal Agents Based on Imidazopyridines.

The present work describes the synthesis of 22 new imidazopyridine analogues arising from medicinal chemistry optimization at different sites on the molecule. Seven and 12 compounds exhibited an in vitro EC50 ≤ 1 µM against Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei) parasites, respectively. Based on promising results of in vitro activity (EC50 < 100 nM), cytotoxicity, metabolic stability, protein binding, and pharmacokinetics (PK) properties, compound 20 was selected as a candidate for in vivo efficacy studies. This compound was screened in an acute mouse model against T.cruzi (Tulahuen strain). After established infection, mice were dosed twice a day for 5 days, and then monitored for 6 weeks using an in vivo imaging system (IVIS). Compound 20 demonstrated parasite inhibition comparable to the benznidazole treatment group. Compound 20 represents a potential lead for the development of drugs to treat trypanosomiasis.

MIA-QSAR modeling of the anti-HIV-1 protease activities and cytotoxicities of ritonavir analogs.

Drug-likeness and toxicity prediction of compounds are so important as to estimate their bioactivities. In rational design of drugs, looking for safe rather than only highly active synthetic targets has increasingly became mandatory. In this context, structure-based methods to model toxicities of drug-like compounds arise as fundamental tasks to achieve safer drugs. Accordingly, the MIA-QSAR method, which has been widely applied to model bioactivities of several classes of compounds, can also be used to predict toxicities of drug-like compounds. In fact, the MIA-based approach has shown to be accurate to model bioactivities, boiling points, NMR chemical shifts and electrophoretic profiles, but it has been used to model cytotoxicities for the first time in this work, in order to contribute for studies to develop safer drugs. The QSAR modeling of bioactivities (pEC50) and cytotoxicities (CCIC50) of a series of HIV-1 protease inhibitors, some ritonavir derivatives, is reported in this work using the MIA-QSAR approach. The statistical quality of both models indicates that pEC50 and CCIC50 of ritonavir analogs can be reliably predicted using this method; therefore, improved drugs can be designed.