[1-7-NαC]-Crocaorb A1 and A2, orbitides from the latex of Croton campanulatus.

Two new heptapeptides, [1-7-NαC]-crocaorbs A1 (1) and A2 (2), were isolated from the latex of Croton campanulatus. Their structures were determined using NMR spectroscopic techniques, ESI-HRMS data, Marfey's method, and further refined using molecular dynamics with simulated annealing (MD/SA). Molecular dynamics calculations of peptides 1 and 2 demonstrated greater stability in simulations using a biological solvent compared to those using DMSO. Compound 1, the most abundant peptide in latex, was assessed for NO production, antiplasmodial and cytotoxicity activities. The peptide significantly increased nitric oxide (NO) production at concentrations of 40, 20 or 10 µM (17.932 ± 1.1, 18.270 ± 0.9, 18.499 ± 0.7, respectively). Its antiplasmodial activity exhibited limited efficacy, with only 5% inhibition of Plasmodium falciparum 3D7 growth at a concentration of 50 µM. Also, it exhibited no cytotoxic effects in the J774A.1 murine macrophages cell line. This study represents the first report of a phytochemical investigation of the species C. campanulatus, which showed orbitides with distinctive sequences in contrast to other peptides described for the genus Croton and contributes to the study of structural diversity within this particular class of compounds.

In silico identification of drug targets and vaccine candidates against Bartonella quintana: a subtractive proteomics approach.

BACKGROUND: The availability of genes and protein sequences for parasites has provided valuable information for drug target identification and vaccine development. One such parasite is Bartonella quintana, a Gram-negative, intracellular pathogen that causes bartonellosis in mammalian hosts. OBJECTIVE: Despite progress in understanding its pathogenesis, limited knowledge exists about the virulence factors and regulatory mechanisms specific to B. quintana. METHODS AND FINDINGS: To explore these aspects, we have adopted a subtractive proteomics approach to analyse the proteome of B. quintana. By subtractive proteins between the host and parasite proteome, a set of proteins that are likely unique to the parasite but absent in the host were identified. This analysis revealed that out of the 1197 protein sequences of the parasite, 660 proteins are non-homologous to the human host. Further analysis using the Database of Essential Genes predicted 159 essential proteins, with 28 of these being unique to the pathogen and predicted as potential putative targets. Subcellular localisation of the predicted targets revealed 13 cytoplasmic, eight membranes, one periplasmic, and multiple location proteins. The three-dimensional structure and B cell epitopes of the six membrane antigenic protein were predicted. Four B cell epitopes in KdtA and mraY proteins, three in lpxB and BQ09550, whereas the ftsl and yidC proteins were located with eleven and six B cell epitopes, respectively. MAINS CONCLUSIONS: This insight prioritises such proteins as novel putative targets for further investigations on their potential as drug and vaccine candidates.

Unravelling carbohydrate binding module 21 (CBM21) dynamics of interaction with amylose.

The carbohydrate binding module 21 (CBM21) from Rhizopus oryzae is a dual-site CBM proposed to disrupt polysaccharide structures. Additionally, it serves as a purification tag in industry. CBM21 crystal structure features a Glc residue in an unusual 1S3 conformation, whose relevance for the CBM mechanism of action is unclear. In this context, we seek to contribute for the understanding of CBM21 mechanism of action by: i) investigating the role of the 1S3 conformation on carbohydrate recognition, and ii) characterize the protein-carbohydrate binding dynamics using molecular dynamics and metadynamics simulations at MM and QM/MM levels. Results indicate the 1S3 Glc conformation is unlikely to occur under biological conditions, being originated from the crystallographic environment. CBM21 binding to small ligands appears transient and unstable, while protein dimerization and polysaccharide chain size influence complex stability. In interactions with amylose, CBM21 exhibits a repeated unbinding followed by re-binding, while simultaneously alternating between binding sites I and II. These results suggest that CBM21 acts through transient interactions, directing carbohydrates to the catalytic center rather than forming strong and long-lasting bonds with carbohydrates. Accordingly, we expect such atomistic depiction of CBM21 mechanism could aid in CBM design targeting biotechnological applications.

SIRAH Late Harvest: Coarse-Grained Models for Protein Glycosylation.

Glycans constitute one of the most complex families of biological molecules. Despite their crucial role in a plethora of biological processes, they remain largely uncharacterized because of their high complexity. Their intrinsic flexibility and the vast variability associated with the many combination possibilities have hampered their experimental determination. Although theoretical methods have proven to be a valid alternative to the study of glycans, the large size associated with polysaccharides, proteoglycans, and glycolipids poses significant challenges to a fully atomistic description of biologically relevant glycoconjugates. On the other hand, the exquisite dependence on hydrogen bonds to determine glycans' structure makes the development of simplified or coarse-grained (CG) representations extremely challenging. This is particularly the case when glycan representations are expected to be compatible with CG force fields that include several molecular types. We introduce a CG representation able to simulate a wide variety of polysaccharides and common glycosylation motifs in proteins, which is fully compatible with the CG SIRAH force field. Examples of application to N-glycosylated proteins, including antibody recognition and calcium-mediated glycan-protein interactions, highlight the versatility of the enlarged set of CG molecules provided by SIRAH.

In silico identification of drug targets and vaccine candidates against Bartonella quintana: a subtractive proteomics approach

BACKGROUND The availability of genes and protein sequences for parasites has provided valuable information for drug target identification and vaccine development. One such parasite is Bartonella quintana, a Gram-negative, intracellular pathogen that causes bartonellosis in mammalian hosts. OBJECTIVE Despite progress in understanding its pathogenesis, limited knowledge exists about the virulence factors and regulatory mechanisms specific to B. quintana. METHODS AND FINDINGS To explore these aspects, we have adopted a subtractive proteomics approach to analyse the proteome of B. quintana. By subtractive proteins between the host and parasite proteome, a set of proteins that are likely unique to the parasite but absent in the host were identified. This analysis revealed that out of the 1197 protein sequences of the parasite, 660 proteins are non-homologous to the human host. Further analysis using the Database of Essential Genes predicted 159 essential proteins, with 28 of these being unique to the pathogen and predicted as potential putative targets. Subcellular localisation of the predicted targets revealed 13 cytoplasmic, eight membranes, one periplasmic, and multiple location proteins. The three-dimensional structure and B cell epitopes of the six membrane antigenic protein were predicted. Four B cell epitopes in KdtA and mraY proteins, three in lpxB and BQ09550, whereas the ftsl and yidC proteins were located with eleven and six B cell epitopes, respectively. MAINS CONCLUSIONS This insight prioritises such proteins as novel putative targets for further investigations on their potential as drug and vaccine candidates.

Theoretical models of staurosporine and analogs uncover detailed structural information in biological solution.

Staurosporine and its analogs (STA-analogs) are indolocarbazoles (ICZs) compounds able to inhibit kinase proteins in a non-specific way, while present antimicrobial and cytostatic properties. The knowledge of molecular features associated to the complexation, including the ligand shape in solution and thermodynamics of complexation, is substantial to the development of new bioactive ICZs with improved therapeutic properties. In this context, the empirical approach of GROMOS force field is able to accurately reproduce condensed phase physicochemical properties of molecular systems after parameterization. Hence, through parameterization under GROMOS force field and molecular simulations, we assessed STA-analogs dynamics in aqueous solution, as well as its interaction with water to probe conformational and structural features involved in complexation to therapeutic targets. The coexistence of multiple conformers observed in simulations, and confirmed by metadynamics calculations, expanding the conformational space knowledge of these ligands with potential implications in understanding the ligand conformational selection during complexation. Also, changes in availability to H-bonding concerning the different substituents and water can reflect on effects at complexation free energy due to variation at the desolvation energetic costs. Based on these results, we expect the obtained structural data provide systemic framework for rational chemical modification of STA-analogs.

Revisiting the structural basis for biological activity of GMI-1070, a sialyl Lewisx mimetic.

When it comes to the treatment of pathologies in which aberrant cell adhesion and extravasation from the bloodstream have been implicated, the selectins represent a central therapeutic target. In this context, the present work investigates the conformational landscape of two prototypes for the design of new antineoplasic and anti-inflammatory agents: the natural selectin ligand sialyl Lewisx and its mimetic GMI-1070. Accordingly, a series of unbiased molecular dynamics simulations at the microsecond scale using GROMOS 53A6 (GLYC), CHARMM36m and GLYCAM06 force fields were employed, together with ConfID, an analytical method for the characterization of conformational populations of small molecules. Our results for sialyl Lewisx are in agreement with and expand upon prior work. As for the mimetic, our results indicate that, in spite of its conformational restriction, GMI-1070's behavior in solution deviates from what had been proposed, highlighting thus some features that could be optimized, as the development of sialyl Lewisx mimetics continues, and new candidates emerge.

L-proline transporter inhibitor (LQFM215) promotes neuroprotection in ischemic stroke.

BACKGROUND: L-proline transporter (PROT/SLC6A7) is closely associated with glutamatergic neurotransmission, where L-proline modulates the NMDA receptor (NMDAR) function. NMDAR-mediated excitotoxicity is a primary cause of neuronal death following stroke, which is triggered by the uncontrolled release of glutamate during the ischemic process. After ischemic stroke, L-proline levels show a reduction in the plasma, but high circulating levels of this molecule indicate good functional recovery. This work aimed to produce new PROT inhibitors and explore their effects on ischemic stroke. METHODS: Initially, we built a three-dimensional model of the PROT protein and run a molecular docking with the newly designed compounds (LQFM215, LQFM216, and LQFM217). Then, we synthesized new PROT inhibitors by molecular hybridization, and proline uptake was measured in ex vivo and in vivo models. The behavioral characterization of the treated mice was performed by the open-field test, elevated plus-maze, Y-maze, and forced swimming test. We used the permanent middle cerebral artery occlusion (MCAO) model to study the ischemic stroke damage and analyzed the motor impairment with limb clasping or cylinder tests. RESULTS: LQFM215 inhibited proline uptake in hippocampal synaptosomes, and the LQFM215 treatment reduced proline levels in the mouse hippocampus. LQFM215 reduced the locomotor and exploratory activity in mice and did not show any anxiety-related or working memory impairments. In the MCAO model, LQFM215 pre-treatment and treatment reduced the infarcted area and reduced motor impairments in the cylinder test and limb clasping. CONCLUSIONS: This dataset suggests that the new compounds inhibit cerebral L-proline uptake and that LQFM215 promotes neuroprotection and neuro-repair in the acute ischemic stroke model.

Structural Characteristics of Glycocins: Unraveling the Role of S-Linked Carbohydrates and Other Structural Elements.

Glycocins are antimicrobial peptides with glycosylations, often an S-linked monosaccharide. Their recent structure elucidation has brought forth questions about their mechanisms of action as well as the impact of S-glycosylation on their structural behavior. Here, we investigated structural characteristics of glycocins using a computational approach. Depending on the peptide's class (sublancin- or glycocin F-like), the sugar changes the peptide's flexibility. Also, the presence of glycosylation is necessary for the lack of structure of Asm1. The C-terminal tail in glycocin F-like peptides influenced their structured regions, acting like a regulator. These findings corroborate the versatility of these post-translational modifications, pointing toward their potential use in molecular engineering.

Neuropharmacological assessment in mice and molecular docking of piperazine derivative LQFM212.

Piperazine derivatives are an attractive class of chemical compounds for the treatment of various mental illness. Herein, we demonstrated the synthesis of LQFM212, a piperazine derivative, behavioral evaluation in mice and computational studies. In neuropharmacological assessment, LQFM212 treatment at doses of 18, 54 or 162 µmol/kg increased the sleep duration in sodium pentobarbital-induced sleep test. LQFM212 at dose of 162 µmol/kg increased climbing time in the chimney test and decreased the number of squares crossed in the open field test, suggesting that LQFM212 in high doses reduces spontaneous movement. However, LQFM212 treatment at the doses of 18 or 54 µmol/kg increased the preference for the center of field which could be indicative of anxiolytic-like effects. In elevated plus maze and light-dark box tests, LQFM212 treatment altered all parameters observed that demonstrate anxiolytic-like activity. These effects were reversed by flumazenil, mecamylamine, WAY-100635 and PCPA, but not with ketanserin, showing that anxiolytic-like activity involve benzodiazepine site of GABAA receptor, nicotinic and serotonergic pathways. Molecular docking of LQFM212 showed that the ligand has more interactions with GABAA receptor than with 5-HT1A receptor. Despite the involvement of benzodiazepine site on anxiolytic-like effect of LQFM212, treatment with this compound did not alter cognitive function in the step-down avoidance test. In this sense, this piperazine derivative is a good prototype for treating anxiety disorders with putative mechanism of action.

Design, synthesis and pharmacological assessment of new pyrazole compounds.

AIMS: This study investigated the antinociceptive and anti-inflammatory effects of new pyrazole compounds LQFM011(5), LQFM043(6) and LQFM044(7) as well as the mechanisms of action and acute in vitro toxicity. MAIN METHODS: The antinociceptive activity was evaluated using the acetic acid-induced abdominal writhing test, formalin-induced pain test and the Randall-Selitto test. The anti-inflammatory activity was evaluated using models of paw oedema and pleurisy induced by carrageenan; cell migration, the levels of tumour necrosis factor α (TNF-α) and myeloperoxidase (MPO) enzyme activity were evaluated. In addition, the ability to inhibit phospholipase A2 (PLA2) in vitro and docking in PLA2 were used. Acute oral systemic toxicity in mice was evaluated through the neutral red uptake assay. KEY FINDINGS: The synthesised compounds (5-7), delivered via gavage (p.o.) at 70, 140 or 280 µmol/kg, decreased the number of writhings induced by acetic acid; the three compounds (280 µmol/kg p.o.) reduced the paw licking time in the first and second phase of the formalin test and decreased the nociceptive threshold variation in the Randall-Selitto test. Furthermore, this dose reduced oedema formation, leucocyte migration (specifically through reduction in polymorphonuclear cell movement) and increased mononuclear cells. MPO activity and the levels of pro-inflammatory cytokines TNF-α were decreased. Evaluation of PLA2 inhibition via the docking simulation revealed more interactions of LQFM043R(6) and LQFM044(7), data that corroborated the half-maximal inhibitory concentration (IC50) of PLA2 inhibition in vitro. Therefore, LQFM011(5), LQFM043(6) and LQFM044(7) were classified with the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) as category 4.

Prediction, mapping and validation of tick glutathione S-transferase B-cell epitopes.

In search of ways to address the increasing incidence of global acaricide resistance, tick control through vaccination is regarded as a sustainable alternative approach. Recently, a novel cocktail antigen tick-vaccine was developed based on the recombinant glutathione S-transferase (rGST) anti-sera cross-reaction to glutathione S-transferases of Rhipicephalus appendiculatus (GST-Ra), Amblyomma variegatum (GST-Av), Haemaphysalis longicornis (GST-Hl), Rhipicephalus decoloratus (GST-Rd) and Rhipicephalus microplus (GST-Rm). Therefore, the current study aimed to predict the shared B-cell epitopes within the GST sequences of these tick species. Prediction of B-cell epitopes and proteasomal cleavage sites were performed using immunoinformatics algorithms. The conserved epitopes predicted within the sequences were mapped on the homodimers of the respective tick GSTs, and the corresponding peptides were independently used for rabbit immunization experiments. Based on the dot blot assay, the immunogenicity of the peptides and their potential to be recognized by corresponding rGST anti-sera raised by rabbit immunization in a previous work were investigated. This study revealed that the predicted conserved B-cell epitopes within the five tick GST sequences were localized on the surface of the respective GST homodimers. The epitopes of GST-Ra, GST-Rd, GST-Av, and GST-Hl were also shown to contain a seven residue-long peptide sequence with no proteasomal cleavage sites, whereas proteasomal digestion of GST-Rm was predicted to yield a 4-residue fragment. Given that a few proteasomal cleavage sites were found within the conserved epitope sequences of the four GSTs, the sequences could also contain a T-cell epitope. Finally, the peptide and rGST anti-sera reacted against the corresponding peptide, confirming their immunogenicity. These data support the claim that the rGSTs, used in the previous study, contain conserved B-cell epitopes, which elucidates why the rGST anti-sera cross-reacted to non-homologous tick GSTs. Taken together, the data suggest that the B-cell epitopes predicted in this study could be useful for constituting epitope-based GST tick vaccines.

A cell surface arabinogalactan-peptide influences root hair cell fate.

Root hairs (RHs) develop from specialized epidermal trichoblast cells, whereas epidermal cells that lack RHs are known as atrichoblasts. The mechanism controlling RH cell fate is only partially understood. RH cell fate is regulated by a transcription factor complex that promotes the expression of the homeodomain protein GLABRA 2 (GL2), which blocks RH development by inhibiting ROOT HAIR DEFECTIVE 6 (RHD6). Suppression of GL2 expression activates RHD6, a series of downstream TFs including ROOT HAIR DEFECTIVE 6 LIKE-4 (RSL4) and their target genes, and causes epidermal cells to develop into RHs. Brassinosteroids (BRs) influence RH cell fate. In the absence of BRs, phosphorylated BIN2 (a Type-II GSK3-like kinase) inhibits a protein complex that regulates GL2 expression. Perturbation of the arabinogalactan peptide (AGP21) in Arabidopsis thaliana triggers aberrant RH development, similar to that observed in plants with defective BR signaling. We reveal that an O-glycosylated AGP21 peptide, which is positively regulated by BZR1, a transcription factor activated by BR signaling, affects RH cell fate by altering GL2 expression in a BIN2-dependent manner. Changes in cell surface AGP disrupts BR responses and inhibits the downstream effect of BIN2 on the RH repressor GL2 in root epidermis.

The Lazy Life of Lipid-Linked Oligosaccharides in All Life Domains.

Lipid-linked oligosaccharides (LLOs) play an important role in the N-glycosylation pathway as the donor substrate of oligosaccharyltransferases (OSTs), which are responsible for the en bloc transfer of glycan chains onto a nascent polypeptide. The lipid component of LLO in both eukarya and archaea consists of a dolichol, and an undecaprenol in prokarya, whereas the number of isoprene units may change between species. Given the potential relevance of LLOs and their related enzymes to diverse biotechnological applications, obtaining reliable LLO models from distinct domains of life could support further studies on complex formation and their processing by OSTs, as well as protein engineering on such systems. In this work, molecular modeling techniques, such as quantum mechanics calculations, molecular dynamics simulations, and metadynamics were employed to study eukaryotic (Glc3-Man9-GlcNAc2-PP-Dolichol), bacterial (Glc1-GalNAc5-Bac1-PP-Undecaprenol), and archaeal (Glc1-Man1-Gal1-Man1-Glc1-Gal1-Glc1-P-Dolichol) LLOs in membrane bilayers. Microsecond molecular dynamics simulations and metadynamics calculations of LLOs revealed that glycan chains are more prone to interact with the membrane lipid head groups, while the PP linkages are positioned at the lipid phosphate head groups level. The dynamics of isoprenoid chains embedded within the bilayer are described, and membrane dynamics and related properties are also investigated. Overall, there are similarities regarding the structure and dynamics of the eukaryotic, the bacterial, and the archaeal LLOs in bilayers, which can support the comprehension of their association with OSTs. These data may support future studies on the transferring mechanism of the oligosaccharide chain to an acceptor protein.

Novel choline analog 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol produces sympathoinhibition, hypotension, and antihypertensive effects.

The search for new drugs remains an important focus for the safe and effective treatment of cardiovascular diseases. Previous evidence has shown that choline analogs can offer therapeutic benefit for cardiovascular complications. The current study investigates the effects of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032) on cardiovascular function and cholinergic-nitric oxide signaling. Synthesized LQFM032 (0.3, 0.6, or 1.2 mg/kg) was administered by intravenous and intracerebroventricular routes to evaluate the potential alteration of mean arterial pressure, heart rate, and renal sympathetic nerve activity of normotensive and hypertensive rats. Vascular function was further evaluated in isolated vessels, while pharmacological antagonists and computational studies of nitric oxide synthase and muscarinic receptors were performed to assess possible mechanisms of LQFM032 activity. The intravenous and intracerebroventricular administration of LQFM032 elicited a temporal reduction in mean arterial pressure, heart rate, and renal sympathetic nerve activity of rats. The cumulative addition of LQFM032 to isolated endothelium-intact aortic rings reduced vascular tension and elicited a concentration-dependent relaxation. Intravenous pretreatment with L-NAME (nitric oxide synthase inhibitor), atropine (nonselective muscarinic receptor antagonist), pirenzepine, and 4-DAMP (muscarinic M1 and M3 subtype receptor antagonist, respectively) attenuated the cardiovascular effects of LQFM032. These changes may be due to a direct regulation of muscarinic signaling as docking data shows an interaction of choline analog with M1 and M3 but not nitric oxide synthase. Together, these findings demonstrate sympathoinhibitory, hypotensive, and antihypertensive effects of LQFM032 and suggest the involvement of muscarinic receptors.

Development of GROMOS-Compatible Parameter Set for Simulations of Chalcones and Flavonoids.

Chalcones and flavonoids constitute a large family of plant secondary metabolites that have been explored as a potential source of novel pharmaceutical products. While the simulation of these compounds by molecular dynamics (MD) can be a valuable strategy to assess their conformational properties and so further develop their role in drug discovery, there are no set of force field parameters specifically designed and experimentally validated for their conformational description in condensed phase. So the current work developed a new parameter set for MD simulations of these compounds' main scaffolds under GROMOS force field. We employed a protocol adjusting the atomic charges and torsional parameters to the respective quantum mechanical derived dipole moments and dihedrals rotational profiles, respectively. Experimental properties of organic liquids were used as references to the calculated values to validate the parameters. Additionally, metadynamics simulations were performed to evaluate the conformational space of complex chalcones and flavonoids, while NOE contacts during simulations were measured and compared to experimental data. Accordingly, the employed protocol allowed us to obtain force field parameters that reproduce well the target data and may be expected to contribute in more accurate computational studies on the biological/therapeutical role of such molecules.

All-Hydrocarbon Staples and Their Effect over Peptide Conformation under Different Force Fields.

Olefinic staples enhance α-helical content and conformational stability in peptides, maintaining a structural scaffold that allows the emulation of specific regions of protein surfaces for therapeutical purposes. The ability to anticipate the efficacy of adding a staple to a peptide through computational simulations may contribute to lowering the costs associated with rational drug design. We evaluated the capabilities of different force fields to reproduce the effect of all-hydrocarbon staples in molecular dynamics simulations. Using the AMBER99SB-ILDN, CHARMM36, and GROMOS54A7 force fields and two distinct initial conformations, we compared our results to experimentally obtained circular dichroism data. The GROMOS54A7 united-atom force field seems to be more accurate compared with all-atom force fields, despite being unable to reproduce the effect of the staple in some of the simulated systems. With further force field enhancements, MD simulations may be used to anticipate conformational effects of all-hydrocarbon staples in peptides.

Molecular docking and pharmacological/toxicological assessment of a new compound designed from celecoxib and paracetamol by molecular hybridization.

Nonsteroidal anti-inflammatory drugs are commonly used worldwide; however, they have several adverse effects, evidencing the need for the development of new, more effective and safe anti-inflammatory and analgesic drugs. This research aimed to design, synthesize and carry out a pharmacological/toxicological investigation of LQFM-102, which was designed from celecoxib and paracetamol by molecular hybridization. To evaluate the analgesic effect of this compound, we performed formalin-induced pain, hot plate and tail flick tests. The anti-inflammatory effect of LQFM-102 was evaluated in carrageenan-induced paw oedema and pleurisy tests. The biochemical markers indicative of toxicity-AST, ALT, GSH, urea and creatinine-as well as the index of gastric lesion after prolonged administration of LQFM-102 were also analyzed. In addition, the interaction of LQFM-102 with COX enzymes was evaluated by molecular docking. In all experimental protocols, celecoxib or paracetamol was used as a positive control at equimolar doses to LQFM-102. LQFM-102 reduced the pain induced by formalin in both phases of the test. However, this compound did not increase the latency to thermal stimuli in the hot plate and tail flick tests, suggesting an involvement of peripheral mechanisms in this effect. Furthermore, LQFM-102 reduced paw oedema, the number of polymorphonuclear cells, myeloperoxidase activity and TNF-α and IL-1ß levels. Another interesting finding was the absence of alterations in the markers of hepatic and renal toxicity or lesions of gastric mucosa. In molecular docking simulations, LQFM-102 interacted with the key residues for activity and potency of cyclooxygenase enzymes, suggesting an inhibition of the activity of these enzymes.

Aromatic Rings Commonly Used in Medicinal Chemistry: Force Fields Comparison and Interactions With Water Toward the Design of New Chemical Entities.

The identification of lead compounds usually includes a step of chemical diversity generation. Its rationale may be supported by both qualitative (SAR) and quantitative (QSAR) approaches, offering models of the putative ligand-receptor interactions. In both scenarios, our understanding of which interactions functional groups can perform is mostly based on their chemical nature (such as electronegativity, volume, melting point, lipophilicity etc.) instead of their dynamics in aqueous, biological solutions (solvent accessibility, lifetime of hydrogen bonds, solvent structure etc.). As a consequence, it is challenging to predict from 2D structures which functional groups will be able to perform interactions with the target receptor, at which intensity and relative abundance in the biological environment, all of which will contribute to ligand potency and intrinsic activity. With this in mind, the aim of this work is to assess properties of aromatic rings, commonly used for drug design, in aqueous solution through molecular dynamics simulations in order to characterize their chemical features and infer their impact in complexation dynamics. For this, common aromatic and heteroaromatic rings were selected and received new atomic charge set based on the direction and module of the dipole moment from MP2/6-31G* calculations, while other topological terms were taken from GROMOS53A6 force field. Afterwards, liquid physicochemical properties were simulated for a calibration set composed by nearly 40 molecules and compared to their respective experimental data, in order to validate each topology. Based on the reliance of the employed strategy, we expanded the dataset to more than 100 aromatic rings. Properties in aqueous solution such as solvent accessible surface area, H-bonds availability, H-bonds residence time, and water structure around heteroatoms were calculated for each ring, creating a database of potential interactions, shedding light on features of drugs in biological solutions, on the structural basis for bioisosterism and on the enthalpic/entropic costs for ligand-receptor complexation dynamics.

Everyone Is a Protagonist: Residue Conformational Preferences in High-Resolution Protein Structures.

In many structural bioinformatics problems, there is a broad range of unanswered questions about protein dynamics and amino acid properties. Proteins are not strictly static objects, but rather populate ensembles of conformations. One way to understand these particularities is to analyze the information available in experimental databases. The Ramachandran plot, despite being more than half a century old, remains an utterly useful tool in the study of protein conformation. Based on its assumptions, we inspected a large data set (11,130 protein structures, amounting to 5,255,768 residues) and discriminated the conformational preferences of each residue type regarding their secondary structure participation. These data were studied for phi [Formula: see text], psi [Formula: see text], and side chain chi [Formula: see text] angles, being presented in non-Ramachandranian plots. In the largest analysis of protein conformation made so far, we propose an original plot to depict conformational preferences in relation to different secondary structure elements. Despite confirming previous observations, our results strongly support a unique character for each residue type, whereas also reinforcing the observation that side chains have a major contribution to secondary structure and, by consequence, on protein conformation. This information can be further used in the development of more robust methods and computational strategies for structural bioinformatics problems.