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Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to AlbuBinder 1 should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.
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Metaloproteasas/metabolismo , Inhibidores de Proteasas/farmacología , Albúmina Sérica Humana/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo , Animales , Proteína Morfogenética Ósea 1/metabolismo , Semivida , Humanos , Ratones , Prueba de Estudio Conceptual , Inhibidores de Proteasas/farmacocinéticaRESUMEN
A series of potent, competitive and highly selective kynurenine monooxygenase inhibitors have been discovered via a substrate-based approach for the treatment of acute pancreatitis. The lead compound demonstrated good cellular potency and clear pharmacodynamic activity in vivo.
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Pancreatitis/tratamiento farmacológico , Animales , Benzoxazoles/química , Benzoxazoles/farmacocinética , Benzoxazoles/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacocinética , Células HEK293 , Humanos , Indazoles/química , Indazoles/farmacocinética , Indazoles/farmacología , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/metabolismo , Pancreatitis/enzimología , Pancreatitis/metabolismo , Ratas , Triptófano/metabolismoRESUMEN
A number of methods to improve the passive permeability of a set of cyclic peptides have been investigated using 6- and 7-mer macrocyclic templates. In many cases the peptides were designed by molecular dynamics calculations to evaluate the methods. The aim of this study was not only to improve passive permeability, but also to balance permeability with other physicochemical properties with the goal of understanding and applying the knowledge to develop active cyclic peptides into drug candidates. Evaluation of the methods herein suggest that increasing passive permeability often occurs at the expense of solubility and lipophilicity. Computational methods can be useful when attempting to predict and design features to balance these properties, though limitations were observed.
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Péptidos Cíclicos/metabolismo , Enlace de Hidrógeno , Péptidos Cíclicos/química , Permeabilidad , Estructura Terciaria de Proteína , Solubilidad , EstereoisomerismoRESUMEN
Introduction: Cysticercosis is a parasitic infestation caused by Taenia solium, which is a pork tape worm. Humans are the definitive host, and pigs are the intermediate host. It is more prevalent in low socioeconomic regions with poor hygiene and among populations where undercooked pork is consumed. Case Presentation: We hereby report an uncommon site of cyst lodgment and duration of presentation in a 24-year-old male who presented with a firm, non-tender mass over the superomedial aspect of the right orbital rim, superior to the medial canthal tendon for the last 9 years. Chronic presentation and location of the mass led to the tentative diagnosis of a dermoid cyst. Hence, a CECT orbit was advised to assess the extent and attachment of the mass. Unexpectedly, a cystic lesion with hyperdense nidus, suggestive of cysticercosis, was identified. Histopathology of the excised mass confirmed the diagnosis of cysticercosis. Conclusion: Our case emphasizes the importance of an uncommon site and chronic presentation in cases of cysticercosis.
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We report the development of BioPhysical and Active Learning Screening (BioPALS); a rapid and versatile hit identification protocol combining AI-powered virtual screening with a GCI-driven biophysical confirmation workflow. Its application to the BRPF1b bromodomain afforded a range of novel micromolar binders with favorable ADMET properties. In addition to the excellent in silico/inâ vitro confirmation rate demonstrated with BRPF1b, binding kinetics were determined, and binding topologies predicted for all hits. BioPALS is a lean, data-rich, and standardized approach to hit identification applicable to a wide range of biological targets.
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Dominios ProteicosRESUMEN
Obesity is an increasingly common disease. While antagonism of the melanin-concentrating hormone-1 receptor (MCH-1R) has been widely reported as a promising therapeutic avenue for obesity treatment, no MCH-1R antagonists have reached the market. Discovery and optimization of new chemical matter targeting MCH-1R is hindered by reduced HTS success rates and a lack of structural information about the MCH-1R binding site. X-ray crystallography and NMR, the major experimental sources of structural information, are very slow processes for membrane proteins and are not currently feasible for every GPCR or GPCR-ligand complex. This situation significantly limits the ability of these methods to impact the drug discovery process for GPCR targets in "real-time", and hence, there is an urgent need for other practical and cost-efficient alternatives. We present here a conceptually pioneering approach that integrates GPCR modeling with design, synthesis, and screening of a diverse library of sugar-based compounds from the VAST technology (versatile assembly on stable templates) to provide structural insights on the MCH-1R binding site. This approach creates a cost-efficient new avenue for structure-based drug discovery (SBDD) against GPCR targets. In our work, a primary VAST hit was used to construct a high-quality MCH-1R model. Following model validation, a structure-based virtual screen yielded a 14% hit rate and 10 novel chemotypes of potent MCH-1R antagonists, including EOAI3367472 (IC50 = 131 nM) and EOAI3367474 (IC50 = 213 nM).
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Fármacos Antiobesidad/farmacología , Carbohidratos/farmacología , Diseño de Fármacos , Obesidad/tratamiento farmacológico , Receptores de Somatostatina/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Secuencia de Aminoácidos , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Fármacos Antiobesidad/uso terapéutico , Sitios de Unión , Carbohidratos/síntesis química , Carbohidratos/química , Carbohidratos/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica , Receptores de Somatostatina/química , Reproducibilidad de los Resultados , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Interfaz Usuario-ComputadorRESUMEN
Direct or type A CCFs are the direct connection between the cavernous segment of the internal carotid artery and the cavernous sinus. While most direct CCFs are caused by trauma, spontaneous direct CCFs are extremely rare in infants. In this report, we describe a 6-month-old child with bulges in the right eye that had been present since 20 days after birth. On examination, there was a right eye abduction limitation with no deviation associated with proptosis. Bruit was present during auscultation. CEMRI showed an enlarged right cavernous sinus with dilatation of the superior ophthalmic vein, suggesting a carotid-cavernous fistula. The patient was referred to an advanced center where he was advised patch therapy to prevent amblyopia. He was kept under observation by a neurosurgeon until 3 years, after which he was scheduled to undergo transarterial coiling.
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The class A G-protein-coupled receptors (GPCRs) Orexin-1 (OX1) and Orexin-2 (OX2) are located predominantly in the brain and are linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuro-endocrine function, and regulation of the sleep-wake cycle. Site-directed mutagenesis (SDM) and domain exchange (chimera) studies have provided important insight into key features of the OX1 and OX2 binding sites. However, the precise determinants of antagonist binding and selectivity are still not fully known. In this work, we used homology modeling of OX receptors to direct further SDM studies. These SDM studies were followed by molecular dynamics (MD) simulations to rationalize the full scope of the SDM data and to explain the role of each mutated residue in the binding and selectivity of a set of OX antagonists: Almorexant (dual OX1 and OX2 antagonist), SB-674042 (OX1 selective antagonist), EMPA (OX2 selective antagonist), and others. Our primary interest was focused on transmembrane helix 3 (TM3), which is identified as being of great importance for the selectivity of OX antagonists. These studies revealed conformational differences between the TM3 helices of OX1 and OX2, resulting from differences in amino acid sequences of the OX receptors that affect key interhelical interactions formed between TM3 and neighboring TM domains. The MD simulation protocol used here, which was followed by flexible docking studies, went beyond the use of static models and allowed for a more detailed exploration of the OX structures. In this work, we have demonstrated how even small differences in the amino acid sequences of GPCRs can lead to significant differences in structure, antagonist binding affinity, and selectivity of these receptors. The MD simulations allowed refinement of the OX receptor models to a degree that was not possible with static homology modeling alone and provided a deeper rationalization of the SDM data obtained. To validate these findings and to demonstrate that they can be usefully applied to the design of novel, very selective OX antagonists, we show here two examples of antagonists designed in house: EP-109-0092 (OX1 selective) and EP-009-0513 (OX2 selective).
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Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/química , Neuropéptidos/antagonistas & inhibidores , Neuropéptidos/química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/química , Secuencia de Aminoácidos , Sitios de Unión , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Modelos Moleculares , Simulación de Dinámica Molecular , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Neuropéptidos/metabolismo , Orexinas , Conformación Proteica , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Matched Molecular Pair Analysis (MMP) is a very important tool during the lead optimization stage in drug discovery. The usefulness of this tool in the lead optimization stage has been discussed in several peer-reviewed articles. The application of MMP in Molecule generation is relatively new. This brings several challenges one of them being the need to encode contextual information into the transforms. In this chapter, we discuss how we use MMPs as a molecule generation method and how does it compare with other molecular generators.
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Descubrimiento de DrogasRESUMEN
Integrins αvß5 and αvß3 are closely related, proangiogenic members of the wider RGD-binding integrin family. Due to their high sequence homology, the development of αvß5-selective compounds has remained elusive to synthetic and medicinal chemists. Herein, we describe a survey of SAR around a series of amide-containing 3-aryl-succinamic acid-based RGD mimetics. This resulted in the discovery of α,α,α-trifluorotolyl 12 which exhibits 800 × selectivity for αvß5versus αvß3 with a pyrrolidine amide linker that confers selectivity for αvß5 by positioning a key aryl ring in the SDL of αvß5 with good complementarity; binding in this mode is disfavoured in αvß3 due to clashes with key residues in the ß3-subunit. Compound 12 exhibits selective inhibition by a cell adhesion assay, high passive permeability and solubility which enables potential use of this inhibitor as an αvß5-selective in vitro tool compound.
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Amidas/farmacología , Pirrolidinas/farmacología , Receptores de Vitronectina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/metabolismo , Adhesión Celular/efectos de los fármacos , Humanos , Células K562 , Simulación del Acoplamiento Molecular , Estructura Molecular , Naftiridinas/síntesis química , Naftiridinas/metabolismo , Naftiridinas/farmacología , Unión Proteica , Pirrolidinas/síntesis química , Pirrolidinas/metabolismo , Receptores de Vitronectina/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 (29b).
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Compuestos Bicíclicos con Puentes/química , Cicloheptanos/química , Morfolinas/química , Fosfatidilinositol 3-Quinasas , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Compuestos Bicíclicos con Puentes/farmacología , Cicloheptanos/farmacología , Descubrimiento de Drogas/métodos , Humanos , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
DNA-encoded library technology (ELT) is a cutting-edge enabling technology platform for drug discovery. Here we describe how to design and synthesize a macrocyclic DNA-encoded library; how to perform selection, sequencing, and data analysis to identify potential active peptides; and how to synthesize off-DNA peptides to confirm activity. This approach provides an effective tool for pharmaceutical research based on peptides.
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ADN/química , Compuestos Macrocíclicos/síntesis química , Biblioteca de Péptidos , Péptidos Cíclicos/química , Descubrimiento de Drogas , Secuenciación de Nucleótidos de Alto Rendimiento , Compuestos Macrocíclicos/química , Péptidos Cíclicos/síntesis química , Dominios y Motivos de Interacción de Proteínas , Bibliotecas de Moléculas Pequeñas/metabolismoRESUMEN
Up to 45 % of deaths in developed nations can be attributed to chronic fibroproliferative diseases, highlighting the need for effective therapies. The RGD (Arg-Gly-Asp) integrin αvß1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identification of non-RGD hit small-molecule αvß1 inhibitors. We show that αvß1 activity is embedded in a range of published α4ß1 (VLA-4) ligands; we also demonstrate how a non-RGD integrin inhibitor (of α4ß1 in this case) was converted into a potent non-zwitterionic RGD integrin inhibitor (of αvß1 in this case). We designed urea ligands with excellent selectivity over α4ß1 and the other αv integrins (αvß3, αvß5, αvß6, αvß8). Inâ silico docking models and density functional theory (DFT) calculations aided the discovery of the lead urea series.
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Fenilalanina/análogos & derivados , Receptores de Vitronectina/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Sitios de Unión , Diseño de Fármacos , Estabilidad de Medicamentos , Humanos , Ligandos , Hígado/metabolismo , Masculino , Fenilalanina/síntesis química , Fenilalanina/metabolismo , Ratas Sprague-Dawley , Receptores de Vitronectina/química , Receptores de Vitronectina/metabolismo , Urea/síntesis química , Urea/metabolismoRESUMEN
A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed.
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Biblioteca de Péptidos , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Proteínas Virales/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Aminoácidos/química , ADN/química , Evaluación Preclínica de Medicamentos/métodos , Terapia Molecular Dirigida , Péptidos Cíclicos/genética , Reacción en Cadena de la Polimerasa , Virus Sincitiales Respiratorios , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/química , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/químicaRESUMEN
In recent rounds of CAPRI, the Bii group has employed a combination of techniques for the prediction of the structure of protein-protein complexes. We currently use third-party software for rigid-body and semiflexible docking (MolFit, 3D-Dock, RosettaDock), and our own steered molecular dynamics (SMD) technique for flexible refinement. SMD has also been found to be useful for discriminating near-native from false positive docking decoys. In addition to this, a variety of sources of information, including multiple descriptors of interface quality combined with a QSAR-like technique, published biological information, and continuum electrostatics calculations, are also used in the assessment of candidate complexes. We shall concentrate on results for CAPRI rounds 9-11 (targets 24-27). In these rounds, the Bii group has been successful in submitting a medium quality model for each of CAPRI targets 25 and 26, and a model of acceptable quality for target 27.
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Biología Computacional/métodos , Simulación por Computador , Mapeo de Interacción de Proteínas , Proteínas/química , Proteómica/métodos , Algoritmos , Cristalografía por Rayos X/métodos , Bases de Datos de Proteínas , Genómica , Conformación Molecular , Unión Proteica , Conformación Proteica , Relación Estructura-Actividad Cuantitativa , Programas Informáticos , Solventes/químicaRESUMEN
The understanding of interactions of poly(ethylene glycol) (PEG) or poly(ethylene oxide) (PEO) with biological interfaces has important technological application in industry and in medicine. In this paper, structural and dynamical properties of PEO at the dimyristoylphospatidylcholine (DMPC) bilayer/water interface have been investigated by molecular dynamics (MD) and steered molecular dynamics (SMD) simulations. The structural properties of a PEO chain in bulk water, at the water/vacuum interface, and in the presence of the membrane were compared with available experimental data. The presence of a barrier for the PEO penetration into the DMPC bilayer has been found. A qualitative estimation of the barrier provided a value equal to approximately 19 kJ/mol, that is, 7 times the value of kT at 310 K.
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Dimiristoilfosfatidilcolina/química , Membrana Dobles de Lípidos , Polietilenglicoles/química , Polímeros/química , Modelos MolecularesRESUMEN
We present results from molecular dynamics simulation of aqueous solutions of alkali halide salts (NaI and NaF) at the interface with hydrophobic objects. The primary objective of this study is to investigate the structural properties of the salt solutions at the hydrophobic surface. An alkane crystal has been taken as the parent model for a hydrophobic surface. A hexagonal hole was created on it, which was half a nm deep and 2.5 nm wide. The density distributions of different species (water, anions, and cations) are studied as a function of distance from the surface. While iodide prefers the interface, the fluoride ions stay inside the bulk water region. The higher concentration of iodide ions at the interface drags sodium counterions to the interface. It also decreases the water density at the interface because of steric effects of the iodide ions. The number of contacts between the surface carbons and water decreases in the case of NaI solutions but is unchanged for NaF solutions. The orientation of the water-ion and the water-water hydrogen bond vector orientations near the interface is discussed in detail.
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BACKGROUND: Conventional topical tretinoin formulation is often associated with local adverse events. Nanogel formulation of tretinoin has good physical stability and enables good penetration of tretinoin into the pilo-sebaceous glands. AIM: The present study was conducted to assess the efficacy and safety of a nanogel formulation of tretinoin as compared to its conventional gel formulation in the treatment of acne vulgaris of the face. MATERIALS AND METHODS: This randomized, active controlled, multicentric, phase IV clinical trial evaluated the treatment of patients with acne vulgaris of the face by the two gel formulations locally applied once daily at night for 12 wk. Acne lesion counts (inflammatory, non-inflammatory & total) and severity grading were carried out on the monthly scheduled visits along with the tolerability assessments. RESULTS: A total of 207 patients were randomized in the study. Reductions in the total (72.9% vs. 65.0%; p = 0.03) and inflammatory (78.1% vs. 66.9%; p = 0.02) acne lesions were reported to be significantly greater with the nanogel formulation as compared to the conventional gel formulation. Local adverse events were significantly less (p = 0.04) in the nanogel group (13.3%) as compared to the conventional gel group (24.7%). Dryness was the most common adverse event reported in both the treatment groups while peeling of skin, burning sensation and photosensitivity were reported in patients using the conventional gel only. CONCLUSION: In the treatment of acne vulgaris of the face, tretinoin nanogel formulation appears to be more effective and better tolerated than the conventional gel formulation.