Recent publications
Chirality plays a crucial role in the biological activity and pharmacological properties of molecules, often leading to significant differences in activity profiles, referred to as chirality cliffs or activity cliffs. To address this challenge, we introduce PyDescriptorC*, a novel Python-based script designed to calculate thousands of chirality-aware descriptors and other molecular descriptors using molecular 3D structures (total 112,194 molecular descriptors). PyDescriptorC* leverages multiprocessing, PyMOL integration, and compatibility with mol2 file formats, ensuring computational efficiency and broad applicability. The tool was rigorously tested on two structurally diverse datasets (HDAC4 and ADM17) for regression analysis, demonstrating exceptional performance in capturing chirality-driven insights and elucidating the molecular basis of chirality cliffs. These chirality descriptors provided a deeper understanding of activity patterns, significantly enhancing the predictive accuracy and interpretability of QSAR models. PyDescriptorC* has been validated across multiple operating systems, ensuring platform independence and user accessibility. This work highlights the potential of PyDescriptorC*, an extended version of PyDescriptor, to advance drug discovery and development by unlocking hidden chirality patterns and bridging the gap between structural data and predictive modelling. Its seamless integration of chirality-specific descriptors into QSAR workflows offers a powerful resource for cheminformatics, machine learning, and molecular design.
This study presents a novel approach to enhance the accuracy of automatic classification systems for airborne pollen particles by integrating domain adaptation techniques. Our method incorporates expert-verified measurements into the convolutional neural network (CNN) training process to address the discrepancy between laboratory test data and real-world environmental measurements. We systematically fine-tuned CNN models, initially developed on standard reference datasets, with these expert-verified measurements. A comprehensive exploration of hyperparameters was conducted to optimize the CNN models, ensuring their robustness and adaptability across various environmental conditions and pollen types. Empirical results indicate a significant improvement, evidenced by a 22.52% increase in correlation and a 38.05% reduction in standard deviation across 29 cases of different pollen classes over multiple study years. This research highlights the potential of domain adaptation techniques in environmental monitoring, particularly in contexts where the integrity and representativeness of reference datasets are difficult to verify.
Due to acidic noxious environment which is present in the gastric lumen, gastric mucosa has evolved several mechanisms that enhance its defense. Nevertheless, in some pathological conditions and in drug-induced gastric injury, this defense barrier is disturbed. Mucosal protective agents are group of drugs synthesized and administered in order to recover the balance of protective and noxious factors in gastric lumen, and protect the gastric mucosa from severe forms of injury. Although, there are other, more often used drugs for this purpose that are preferred in clinical practice, in some cases, mucosal protective agents are first-line therapy. Misoprostol, sucralfate and bismuth are capable of enhancing mucosal defense through various mechanisms. However, these agents may cause numerous side effects as well. Therefore, before administering these drugs to patients, clinicians have to calculate risk and benefit ratio for the patient and make an adequate decision.
The clinical practice already observes substantial gain in applying pharmacogenomics (PGx) testing to the optimization of drug therapy, particularly in identifying responders and nonresponders to medications, avoiding adverse events, and optimizing drug doses. Dosage adjustments according to the patient’s genotype for certain drugs and drug classes have been already implemented in relevant clinical guidelines. For example, many pharmacogenomic biomarkers’ genetic variants that demonstrated clinical utility are already incorporated into drug labels. In recent years, personalized management of gastrointestinal disorders based on pharmacogenomics has become a reality. In this chapter, we review the clinical pharmacogenomics of drugs used for the treatment of nonmalignant disorders of the gastrointestinal tract such as proton pump inhibitors, antiemetics, and drugs used to treat inflammatory bowel diseases. For some drugs, such as serotonin 5-HT3 antagonists, proton pump inhibitors, and thiopurines, evidence-based guidelines recommend dosage adjustment according to a patient genotype, while for others, the role of PGx testing to improve therapy outcomes is still a matter of investigation.
Cytochrome P450 enzymes may be induced or inhibited depending on gene polymorphism and metabolized drugs, thus leading to possible drug-drug interactions (DDI) that can cause adverse drug reactions (ADR) and failure in therapy. The enzymes involved in drug metabolism are classified as phase I and phase II metabolism enzymes. The enzymes CYP2C19, CYP2C9, CYP2D6, CYP3A and their polymorphisms are clinically the most important and most studied enzymes of this superfamily and are responsible for metabolizing around 80% of currently used drugs. Transporter-mediated DDI is not that common, but nonetheless they should be considered in clinical practice. They are mediated through inhibition or activation of two major superfamilies, ATP binding cassette and solute carrier transporters. Drug therapies can lead to functional alterations in specific transporters which are expressed in different tissues, specifically blood-brain barrier, placenta, cancer cells, kidneys and liver, causing changes in their substrate drug transport.
Proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) are among most commonly used and overprescribed drugs worldwide. They are used for treatment of acid-related conditions. H2RAs were the first and very effective group of medications used for the therapy of acid-peptic disease and their safety and efficacy led to their availability without a prescription.
PPIs were long considered to have a very good safety profile. However, in recent years chronic PPI use has been associated with several serious side effects, such as increased fracture risk and risk of cardiovascular and cerebrovascular events. Many of those findings resulted from observational studies and further investigations are needed to elucidate the mechanisms behind the findings and reveal their clinical relevance.
Drug-drug interactions (DDIs) comes as a result of action two or more drugs taken simultaneously by the same patient. They can be clinically relevant or no. Treatment failure or drug toxicity can be a consequence of significant DDIs. Assessment of DDIs is one of the most important steps in a process of the development of a new molecular entity as well as the future risk-benefit evaluation. The main regulatory bodies like European Medical Agency (EMA), US Food and Drug Administration (FDA), and Japanese Pharmaceuticals and Medical Device Agency (PDMA) made guidelines with detailed recommendations to recognize DDIs using different type tests (in silico, in vitro, preclinical and clinical) to assess DDI risk and informed the patient about proper management. The advanced in vitro methodology and modeling significantly improved our knowledge and understanding of DDI mechanisms and tools for recognizing and predicting them. The evaluation of DDI risk includes a clinical DDI study, as a central part of the process. Moreover, clinical DDI studies are a powerful tool for detecting DDIs and help us to explain their mechanisms, which can be confirmed by in vitro methods through the process of reverse translation. DDI clinical assessment cannot cover each permutation of different parameters involved in the outcome. In silico models together with mechanistically focused clinical development are the basis for understanding the clinical relevance of DDIs. There is no standard and optimal schedule to examine DDIs, but the design of each study has to be grounded carefully, based on the availability of in vitro and clinical data, to ensure the usefulness of the study and protect the subject’s safety. This chapter tries to follow an assessment of DDI through the drug development process.
Medications possess significant health risks including ADEs, MEs, adverse drug reactions (ADR), DDIs, and other outcomes of nonoptimized drug use, defined commonly as drug-related problems. Due to nonstandardized use of these terms, comparing studies and calculating a rate of incidence is sometimes “impossible mission.” ADRs can be described as an unwanted harmful reaction that occur following drug application and suspected to be drug related. The recent definition of ADR including reactions those resulting from MEs, abuse, or misuse, as well reactions to unlicensed medicine, off-label use in addition to use of authorized medicines according to label. DDIs can change drug action caused by concomitant administration one or more drugs, and they can be harmful and fatal. The estimated mean of health care cost due to nonoptimized medication used was 528.4 billion USD in 2016. This sum was equivalent to 16% of total US health care expenditure.
When the effect of a particular drug is influenced by the presence of another drug, food or herbal product, it means an interaction between them has occurred. The interaction can result in favorable or unfavorable effects. Certain drug-drug interactions are intentionally provoked to achieve stronger therapeutic effects, e.g., in the treatment of hypertension, pain, bronchial asthma, or complex infections. However, drug-drug interactions oftentimes cause adverse effects or reduce the action of a particular drug. Drug-drug interactions are divided into three main groups: pharmacodynamic, pharmacokinetic and combined.
Immune-mediated disorders (IMDs) consist of a wide spectrum of gastrointestinal and extraintestinal disorders. Deregulation of immune response and chronic inflammation have a crucial role in the development of infectious, inflammatory, and autoimmune diseases which affect abdominal organs as well. The etiology of these diseases is multifactorial including environmental factors, dietary habits, and pathogens in genetically susceptible patients. It causes injuries to the tissue and organs in the gastrointestinal tract, affected due to the excessive and uncontrolled inflammation. Over the past decade, our knowledge of underlying molecular and pathophysiological mechanisms that lead to IMDs has greatly advanced. It is now understood that interruption in the regulation of innate and adaptive immunity caused by environmental triggers in genetically predisposed individuals can set off an inappropriate or excessive immune response that can lead to the destruction of tissue or organs. Overall in IMDs, a TH1 immune response and also a reduction of the differentiation to the TH2 response are dominant. Once an antigen in IMDs initiates the inflammatory response, higher production of pro-inflammatory cytokines is observed such as TNF-α, IL-1, and IL-6, and the reduction of other cytokines such as IL-10 and IL-4. In the past three decades, remarkable advances have been made in the ability to target specific components of the immune and inflammatory response providing superior treatments for IMDs.
The safety of drugs is a frequent concern in patient management. This is also the case in cirrhotic patients which represent the challenging population of patients to manage. Currently, there are no guidelines for medical management of liver cirrhosis patients. According to data, adjustment of drug dosage in patients with liver disease should be considered according to the Child-Pugh score. The liver is one of the central organs which has an important role in drug absorption, but also in drug distribution and elimination. The liver affects pharmacokinetics and pharmacodynamics not just through the process of biotransformation but also through processes of blood flow through the liver, the binding capacity of plasma proteins and the excretion of drugs throughout the biliary system, all of which can be highly significant. Therefore, management of this specific group of patients is complicated, and an individual approach is warranted.
There are three main groups of acid suppressant drugs containing antacids, histamine H2 receptor antagonists, and proton pump inhibitors. Their role is to elevate gastric pH through different mechanisms and with different duration of action, from short-acting antacids to PPI which have the longest duration of acid suppression. Other drugs used for treating acid-related disorders also include sucralfate, bismuth, and prostaglandin analogues. All of them can interact with other drugs affecting their absorption, metabolism, and elimination. As gastric acid-reducing agents are commonly used to treat conditions pertaining to gastrointestinal disease in all age groups, we will review possible interactions with the most common orally administered medications taking into consideration potential comorbidities we can expect in our everyday practices.
Gastrointestinal diseases are closely related to endocrine disorders, and because of that a multidisciplinary approach is necessary for the diagnosis and treatment for that type of patients. The prevalence of obesity, type 2 diabetes, and nonalcoholic fatty liver disease has been increasing rapidly in recent decades, leaving behind negative effects on organ systems. The number of patients with metabolic syndrome, which includes the centripetal type of obesity, arterial hypertension, insulin resistance, and atherogenic dyslipidemia, are also growing due to urbanization and a sedentary lifestyle. Pathophysiological mechanisms in metabolic disorders are complex, and there is no single cause, so the imperative is to take a holistic approach to each patient.
Certain gastrointestinal disorders could present with a diverse number of neurological signs and symptoms resembling different neurological conditions. In a distinct number of patients, the first sign of underlying gastrointestinal disease could be a neurological sign or symptom indicating a neurological problem. There are some specific neurological symptoms which are frequently seen with distinct gastrointestinal disorders, but in many other cases no specific sign or symptom could lead a neurologist to a suspicion on a gastrointestinal disorder which is most frequently diagnosed only after all neurological causes of patients′ symptoms have been excluded. On the other hand, gastrointestinal disorders of unknown cause could sometimes resemble certain neurological disorders. Hence, it is important for both gastroenterologists and neurologists to be familiar with conditions which could present with symptoms characteristic of both systems. In this chapter, we will present the most frequent conditions in which symptoms overlap between neurology and gastroenterology.
The present study aimed to assess the mechanisms of flow-induced dilation (FID) altered by acute/intermittent hyperbaric oxygenation (HBO 2 ) in isolated middle cerebral arteries of healthy male Sprague–Dawley rats ( n = 96) and randomized to the Ac-HBO 2 group (exposed to a single HBO 2 session, 120 minutes of 100% O 2 at 2.0 bars), the 4Dys-HBO 2 group (4 consecutive days of single HBO 2 sessions, analyzed on the fifth day), and the CTRL (untreated) group. Results demonstrated increased vascular oxidative stress and decreased vascular nitric oxide bioavailability, as measured by direct fluorescence microscopy, leading to attenuated FID in the Ac-HBO 2 group compared with the CTRL and 4Dys-HBO 2 groups. Superoxide scavenging restored FID. Moreover, the increased expression of antioxidative enzymes in the cerebral vasculature in the 4Dys-HBO 2 group indicates the ability of intermittent HBO 2 to activate antioxidative mechanisms. Importantly, the results suggest a switch or at least activation of the compensatory mechanism of FID after HBO 2 from nitric oxide-dependent to epoxygenase metabolite-mediated via TRPV4 (transient receptor potential cation channel subfamily V member 4) and potassium channels, as demonstrated by increased protein expression of KCNMB1 (potassium calcium-activated channel subfamily M regulatory beta subunit 1), TRPV4, and Kir2 (a component of the inward rectifier-type potassium channel Kir2) in the vasculature. Overall, acute HBO 2 modulates FID in cerebral vessels by increasing oxidative stress and altering the subsequent mechanisms of FID, which are mainly mediated by nitric oxide, while suppressing potassium and TRPV4 channel function/expression due to increased oxidative stress. Moreover, intermittent HBO 2 activates antioxidative mechanisms and the compensatory mechanism of FID from nitric oxide-dependent to epoxygenase metabolite-mediated mechanisms via TRPV4, KCNMB1 and Kir2.1.
Extracellular vesicles are a group of heterogeneous particles secreted during both physiological and pathological conditions which serve in intercellular communication and play a role in the development and progression of oral squamous cell carcinoma, the most common malignant tumor of the head and neck with a high mortality rate. Extensive research is being conducted in order to determine the precise role of extracellular vesicles in oncogenic processes and to explore the possible application of extracellular vesicles as early tumor biomarkers. In this review, we aimed to systematize observed roles extracellular vesicles might play in organizing of tumor microenvironment, tumor invasion and metastasis, as well as the impact of extracellular vesicles on immune dysregulation and development of resistance to chemotherapeutics. Additionally, we summarized findings involving the potential use of extracellular vesicles cargo proteins as early disease biomarkers.
Despite advancements in molecular design rules and understanding biochemical processes, the field of drug design and discovery seeks to minimize the number and duration of synthesis‐testing cycles to convert lead compounds into drug candidates. A promising strategy involves gaining insightful understanding of key heteroatoms such as oxygen and nitrogen. This work presents a comprehensive analysis of oxygen atoms in approved drugs, aiming to streamline drug design and discovery efforts. The study examines the frequency, distribution, prevalence, and diversity of oxygen atoms in a dataset of 2049 small molecules approved by the FDA and other agencies. The analysis focuses on various types of oxygen atoms, including sp ³ , sp ² ‐hybridized, ring, and nonring. In general, existence of sp ³ ‐O slightly outperforms sp ² ‐O, which is associated with balancing various factors such as flexibility, solubility, stability, and pharmacokinetics, in addition to activity and selectivity. In approved drugs, majority of oxygen atoms are present within 4 Å from the COM of the molecule. This analysis offers valuable understanding of oxygen distribution, which could be used during the multiparameter optimization process, facilitating the transformation of a hit/lead compound into a potential drug candidate.
Institution pages aggregate content on ResearchGate related to an institution. The members listed on this page have self-identified as being affiliated with this institution. Publications listed on this page were identified by our algorithms as relating to this institution. This page was not created or approved by the institution. If you represent an institution and have questions about these pages or wish to report inaccurate content, you can contact us here.
Information
Address
Osijek, Croatia