Between Theory and Practice: Computational/Experimental Integrated Approaches to Understand the Solubility and Lipophilicity of PROTACs.

Emerging drug candidates more often fall in the beyond-rule-of-five chemical space. Among them, proteolysis targeting chimeras (PROTACs) have gained great attention in the past decade. Although physicochemical properties of small molecules accomplishing Lipinski's rule-of-five can now be easily predicted through models generated by large data collections, for PROTACs the knowledge is still limited and heterogeneous, hampering their prediction.

Cytotoxicity on low-grade canine meningioma with the use of somatostatin analog (octreotide): An in vitro study.

Background: Meningioma is the most common tumor of the central nervous system of dogs. For this tumor, surgery remains the treatment of choice, either alone or in combination with radiotherapy. Unfortunately, chemotherapeutic strategies are practically absent in dogs and palliative therapies are the only option to surgery.

Identification of small molecules affecting the interaction between human hemoglobin and Staphylococcus aureus IsdB hemophore.

Human hemoglobin (Hb) is the preferred iron source of Staphylococcus aureus. This pathogenic bacterium exploits a sophisticated protein machinery called Iron-regulated surface determinant (Isd) system to bind Hb, extract and internalize heme, and finally degrade it to complete iron acquisition. IsdB, the surface exposed Hb receptor, is a proven virulence factor of S.

Targeting protein-protein interactions with low molecular weight and short peptide modulators: insights on disease pathways and starting points for drug discovery.

Introduction: Protein-protein interactions (PPIs) have been often considered undruggable targets although they are attractive for the discovery of new therapeutics. The spread of artificial intelligence and machine learning complemented with experimental methods is likely to change the perspectives of protein-protein modulator research. Noteworthy, some novel low molecular weight (LMW) and short peptide modulators of PPIs are already in clinical trials for the treatment of relevant diseases.

An Integrated Machine Learning Model To Spot Peptide Binding Pockets in 3D Protein Screening.

The prediction of peptide-protein binding sites is of utmost importance to tackle the onset of severe neurodegenerative diseases and cancer. In this work, we detail a novel machine learning model based on Linear Discriminant Analysis (LDA) demonstrating to be highly predictive in detecting the putative protein binding regions of small peptides. Starting from 439 high-quality pockets derived from peptide-protein crystallographic complexes, three sets of well-established peptide-binding regions were first selected through a Partitioning Around Medoids (PAM) clustering algorithm based on morphological and energetic 3D GRID-MIF molecular descriptors.

Analytical and computational workflow for in-depth analysis of oxidized complex lipids in blood plasma.

Lipids are a structurally diverse class of biomolecules which can undergo a variety of chemical modifications. Among them, lipid (per)oxidation attracts most of the attention due to its significance in the regulation of inflammation, cell proliferation and death programs. Despite their apparent regulatory significance, the molecular repertoire of oxidized lipids remains largely elusive as accurate annotation of lipid modifications is complicated by their low abundance and often unknown, biological context-dependent structural diversity.

Exploring Ligand Binding Domain Dynamics in the NRs Superfamily.

Nuclear receptors (NRs) are transcription factors that play an important role in multiple diseases, such as cancer, inflammation, and metabolic disorders. They share a common structural organization composed of five domains, of which the ligand-binding domain (LBD) can adopt different conformations in response to substrate, agonist, and antagonist binding, leading to distinct transcription effects. A key feature of NRs is, indeed, their intrinsic dynamics that make them a challenging target in drug discovery.

Prevalence, clinical features, and outcome of intervertebral disc extrusion associated with extensive epidural hemorrhage in a population of French Bulldogs compared to Dachshunds.

Intervertebral disc extrusion associated with extensive epidural hemorrhage (DEEH) is a well-documented pathological condition in veterinary medicine. This retrospective study aimed to evaluate the prevalence and clinical features of DEEH in a population of French Bulldogs affected by intervertebral disc extrusion (n=75), compare the findings with those from a group of Dachshunds (n=98) and identify possible predictive factors of DEEH and outcomes in surgically treated patients. The study showed that the prevalence of DEEH observed in Dachshunds (11.

ELIOT: A platform to navigate the E3 pocketome and aid the design of new PROTACs.

Proteolysis-targeting chimeras (PROTACs) are novel therapeutics for the treatment of human disease. They exploit the enormous potential of the E3 ligases, a class of proteins that mark a target protein for degradation via the ubiquitin-proteasome system. Despite the existence of several E3 ligase-related databases, the choice of the functioning ligase is limited to only 1.

CROMATIC: ss-Relationship p of Cavies from oronaviruses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19 disease, has rapidly imposed an urgent need to identify effective drug candidates. In this context, the high resolution and non-redundant beta-Coronavirus protein cavities database is pivotal to help virtual screening protocols. Furthermore, the cross-relationship among cavities can lead to highlighting multitarget therapy chances.

Getting Insights into Structural and Energetic Properties of Reciprocal Peptide-Protein Interactions.

Peptide-protein interactions play a key role for many cellular and metabolic processes involved in the onset of largely spread diseases such as cancer and neurodegenerative pathologies. Despite the progress in the structural characterization of peptide-protein interfaces, the in-depth knowledge of the molecular details behind their interactions is still a daunting task. Here, we present the first comprehensive morphological and energetic study of peptide binding sites by focusing on both peptide and protein standpoints.

Indomethacin-based PROTACs as pan-coronavirus antiviral agents.

Indomethacin (INM), a well-known non-steroidal anti-inflammatory drug, has recently gained attention for its antiviral activity demonstrated in drug repurposing studies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Although the mechanism of action of INM is not yet fully understood, recent studies have indicated that it acts at an early stage of the coronaviruses (CoVs) replication cycle. In addition, a proteomic study reported that the anti-SARS-CoV-2 activity of INM could be also ascribed to its ability to inhibit human prostaglandin E synthase type 2 (PGES-2), a host protein which interacts with the SARS-CoV-2 NSP7 protein.

Incidence and type of brain herniation associated with intracranial meningioma in dogs and cats.

The incidence of brain herniation (BH) in association with intracranial meningioma (ICM) in dogs and cats is poorly described. The aim of this study was to evaluate the rate and type of brain herniations in client-owned dogs and cats with ICMs and to determine the meningioma volume (MV) relative to cranial cavity volume (CCV). A retrospective magnetic resonance imaging (MRI) analysis study of 24 cats and 45 dogs with ICMs was conducted to ascertain the presence and characteristics of BH.

Clinical features of muscle cramp in 14 dogs.

Background: Muscle cramps (MCs) are prolonged, involuntary, painful muscle contractions characterized by an acute onset and short duration, caused by peripheral nerve hyperactivity.

Objectives: To provide a detailed description of the clinical features and diagnostic findings in dogs affected by MCs.

Animals: Fourteen dogs.

Neurological abnormalities in 97 dogs with detectable pituitary masses.

Pituitary tumours are common neoplasms of the sellar region in small animals. However, detailed information regarding the spectrum and severity of possible neurological signs are lacking. To retrospectively describe the neurological abnormalities in a population of dogs with a detectable pituitary mass (DPM) and relate them with the size of the mass and magnetic resonance imaging (MRI) signs of brain compression (BC).

Central nervous system metastasis of an intradural malignant peripheral nerve sheath tumor in a dog.

An 8-yr-old French Bulldog was presented with a non-ambulatory tetraparesis. Magnetic resonance showed an intradurally located mass at the level of the right second cervical nerve root. The mass was surgically removed and the dog was ambulatory within 4 d.

Discovering New Casein Kinase 1d Inhibitors with an Innovative Molecular Dynamics Enabled Virtual Screening Workflow.

The value of including protein flexibility in structure-based drug design (SBDD) is widely documented, and currently, molecular dynamics (MD) simulations represent a powerful tool to investigate protein dynamics. Yet, the inclusion of MD-derived information in pre-existing SBDD workflows is still far from trivial. We recently published an integrated MD-FLAP (Fingerprints for Ligands and Proteins) approach combining MD, clustering and Linear Discriminant Analysis (LDA) for enhancing accuracy, efficacy, and for protein conformational selection in virtual screening (VS) campaigns.

First virtual screening and experimental validation of inhibitors targeting GES-5 carbapenemase.

The worldwide spread of beta-lactamases with hydrolytic activity extended to last resort carbapenems is aggravating the antibiotic resistance problem and endangers the successful antimicrobial treatment of clinically relevant pathogens. As recently highlighted by the World Health Organization, new strategies to contain antimicrobial resistance are urgently needed. Class A carbapenemases include members of the KPC, GES and SFC families.

From Experiments to a Fast Easy-to-Use Computational Methodology to Predict Human Aldehyde Oxidase Selectivity and Metabolic Reactions.

Aldehyde oxidase (AOX) is a molibdo-flavoenzyme that has raised great interest in recent years, since its contribution in xenobiotic metabolism has not always been identified before clinical trials, with consequent negative effects on the fate of new potential drugs. The fundamental role of AOX in metabolizing xenobiotics is also due to the attempt of medicinal chemists to stabilize candidates toward cytochrome P450 activity, which increases the risk for new compounds to be susceptible to AOX nucleophile attack. Therefore, novel strategies to predict the potential liability of new entities toward the AOX enzyme are urgently needed to increase effectiveness, reduce costs, and prioritize experimental studies.

Nodo-paranodopathy, internodopathy and cleftopathy: Target-based reclassification of Guillain-Barré-like immune-mediated polyradiculoneuropathies in dogs and cats.

Recent views on Guillain-Barré syndrome (GBS) question the accuracy of classification into axonal and demyelinating subtypes that represent convergent neurophysiological phenotypes rather than immunological targets. Instead it has been proposed to clarify the primarily affected fibre subunit in nerve biopsies. As nerve biopsies rarely are part of routine work-up in human patients we evaluated tissues taken from companion animals affected by GBS-like polyradiculoneuropathy to screen for distribution of immune cells, targeted fibre components and segregating non-inflammatory lesions.

Dorsal midbrain syndrome associated with persistent neck extension: Clinical and diagnostic imaging findings in 2 dogs.

Two young dogs were evaluated for an acute onset of abnormal head posture and eye movement. Neurological examination was characterized mostly by permanent neck extension, abnormalities of pupils, and eye movement. A mesencephalic mass lesion was detected on magnetic resonance imaging in both cases.

A Pipeline To Enhance Ligand Virtual Screening: Integrating Molecular Dynamics and Fingerprints for Ligand and Proteins.

The importance of taking into account protein flexibility in drug design and virtual ligand screening (VS) has been widely debated in the literature, and molecular dynamics (MD) has been recognized as one of the most powerful tools for investigating intrinsic protein dynamics. Nevertheless, deciphering the amount of information hidden in MD simulations and recognizing a significant minimal set of states to be used in virtual screening experiments can be quite complicated. Here we present an integrated MD-FLAP (molecular dynamics-fingerprints for ligand and proteins) approach, comprising a pipeline of molecular dynamics, clustering and linear discriminant analysis, for enhancing accuracy and efficacy in VS campaigns.

Papillary meningioma in the dog: A clinicopathological case series study.

Papillary meningioma (PM) is one of the most aggressive variants of meningioma in humans and classified as grade III by WHO system. To date, the biological behavior of PM is still not clear in dogs. This study investigated the correlation between histopathological findings of 16 canine PMs and follow up data.

BioGPS: navigating biological space to predict polypharmacology, off-targeting, and selectivity.

The structural comparison of protein binding sites is increasingly important in drug design; identifying structurally similar sites can be useful for techniques such as drug repurposing, and also in a polypharmacological approach to deliberately affect multiple targets in a disease pathway, or to explain unwanted off-target effects. Once similar sites are identified, identifying local differences can aid in the design of selectivity. Such an approach moves away from the classical "one target one drug" approach and toward a wider systems biology paradigm.