Virtual screening

BACKGROUND: Lysine-specific demethylase 1 (LSD1) is highly expressed in a variety of malignant tumors, rendering it a crucial epigenetic target for anti-tumor therapy. Therefore, the inhibition of LSD1 activity has emerged as a promising innovative therapeutic approach for targeted cancer treatment. METHODS: In our study, we employed innovative structure-based drug design methods to meticulously select compounds from the ZINC15 database. Utilizing virtual docking, we evaluated docking scores and binding modes to identify potential inhibitors...

Dysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity. Inhibition of the NSD2-PWWP1 domain using small molecules has been considered as an alternative approach to reduce NSD2-unregulated activity...

Cardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low-density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid-lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein-protein interactions with low-density lipoprotein, making it a critical target for designing promising inhibitors compared to statins...

The equivalence of absorption rates and extents between generic drugs and their reference formulations is crucial for ensuring therapeutic comparability. Bioequivalence (BE) studies are widely utilized and play a pivotal role in substantiating the approval and promotional efforts for generic drugs. Virtual BE simulation is a valuable tool for mitigating risks and guiding clinical BE studies, thereby minimizing redundant in vivo BE assessments. Herein, we successfully developed a physiologically based absorption model for virtual BE simulations, which precisely predicts the BE of the apixaban test and reference formulations...

Rapid advances in medical imaging Artificial Intelligence (AI) offer unprecedented opportunities for automatic analysis and extraction of data from large imaging collections. Computational demands of such modern AI tools may be difficult to satisfy with the capabilities available on premises. Cloud computing offers the promise of economical access and extreme scalability. Few studies examine the price/performance tradeoffs of using the cloud, in particular for medical image analysis tasks. We investigate the use of cloud-provisioned compute resources for AI-based curation of the National Lung Screening Trial (NLST) Computed Tomography (CT) images available from the National Cancer Institute (NCI) Imaging Data Commons (IDC)...

Access to quality healthcare remains a challenge in low-and middle-income countries. Vulnerable populations with unmet needs face the greatest challenge in accessing primary care for appropriate and timely healthcare. The use of digital technologies can not only strengthen health systems but also improve access to health care, particularly for the vulnerable. This scoping review aims to assess the various digital health technologies and interventions available for improving access to primary care for the vulnerable in India...

Objective: This study aims to explore the predictive value of T2-weighted imaging (T2WI), apparent diffusion coefficient (ADC), and early-delayed phases enhanced magnetic resonance imaging (DCE-MRI) radiomics prediction model in determining human epidermal growth factor receptor 2 status in breast cancer. Methods: A retrospective study was conducted, involving 187 patients with confirmed breast cancer by postsurgical pathology at Zhenjiang First People's Hospital during January 2021 and May 2023. Immunohistochemistry or fluorescence in situ hybridization was used to determine the HER-2 status of these patients, with 48 cases classified as HER-2 positive and 139 cases as HER-2 negative...

Molecular fingerprints are indispensable tools in cheminformatics. However, stereochemistry is generally not considered, which is problematic for large molecules which are almost all chiral. Herein we report MAP4C, a chiral version of our previously reported fingerprint MAP4, which lists MinHashes computed from character strings containing the SMILES of all pairs of circular substructures up to a diameter of four bonds and the shortest topological distance between their central atoms. MAP4C includes the Cahn-Ingold-Prelog (CIP) annotation (R, S, r or s) whenever the chiral atom is the center of a circular substructure, a question mark for undefined stereocenters, and double bond cis-trans information if specified...

To unlock the full promise of messenger (mRNA) therapies, expanding the toolkit of lipid nanoparticles is paramount. However, a pivotal component of lipid nanoparticle development that remains a bottleneck is identifying new ionizable lipids. Here we describe an accelerated approach to discovering effective ionizable lipids for mRNA delivery that combines machine learning with advanced combinatorial chemistry tools. Starting from a simple four-component reaction platform, we create a chemically diverse library of 584 ionizable lipids...

The aim of this study is to validate the activity of hazelnut ( Corylus avellana L. )-derived immunoactive peptides inhibiting the main protease (Mpro ) of SARS-CoV-2 and further unveil their interaction mechanism using in vitro assays, molecular dynamics (MD) simulations, and binding free energy calculations. In general, the enzymatic hydrolysis components, especially molecular weight < 3 kDa, possess good immune activity as measured by the proliferation ability of mouse splenic lymphocytes and phagocytic activity of mouse peritoneal macrophages...

Inductive bias in machine learning (ML) is the set of assumptions describing how a model makes predictions. Different ML-based methods for protein-ligand binding affinity (PLA) prediction have different inductive biases, leading to different levels of generalization capability and interpretability. Intuitively, the inductive bias of an ML-based model for PLA prediction should fit in with biological mechanisms relevant for binding to achieve good predictions with meaningful reasons. To this end, we propose an interaction-based inductive bias to restrict neural networks to functions relevant for binding with two assumptions: (1) A protein-ligand complex can be naturally expressed as a heterogeneous graph with covalent and non-covalent interactions; (2) The predicted PLA is the sum of pairwise atom-atom affinities determined by non-covalent interactions...

To understand the surface evolution and potential habitability of other planets we must analyse their geology - the 3D structure and chemistry of the rocks that are exposed at the surface. Although rovers capture this 3D structure using stereo camera systems and other instruments, when we present this information to mission scientists for analysis it is generally confined to the 2D plane of a computer screen, and the spatial information is lost at the point when it is needed most. To address this problem, we design, develop, and evaluate a prototype Virtual Environment to present geological data in the 3D form in which it was originally captured, and users are supplied with a toolkit for measurement and annotation of data...

INTRODUCTION: Musculoskeletal pain and opioid misuse frequently co-occur. REVIEW OF THE LITERATURE: The US Preventive Services Task Force calls for all health care providers to be trained to screen for misuse and/or opioid use disorder. The purpose of this study was to develop and implement an opioid misuse training program that could be used by physical therapists. SUBJECTS: Thirteen practicing physical therapists were invited to participate in a curriculum development project...

BACKGROUND: Since 2003, a decline in the age-standardized incidence rates of colorectal cancer (CRC) has been observed in Germany. Nonetheless, one in eight cancer cases still affects the colon or rectum. The prognosis has improved, with the relative 5‑year survival rate for CRC being approximately 65%. METHODS: This positive trend is probably a result of preventive measures introduced over the last 20 years. This could be further improved, however, as CRC can not only be detected early but in almost all cases also prevented through the identification of benign precursors...

Precision dosing strategies require accounting for between-patient variability in pharmacokinetics (PK), affecting drug exposure, and in pharmacodynamics (PD), affecting response achieved at the same drug concentration at the site of action. Although liquid biopsy for assessing different levels of molecular drug targets has yet to be established, individual characterization of drug elimination pathways using liquid biopsy has recently been demonstrated. The feasibility of applying this approach in conjunction with modeling tools to guide individual dosing remains unexplored...

Aldose reductase plays a central role in diabetes mellitus (DM) associated complications by converting glucose to sorbitol, resulting in a harmful increase of reactive oxygen species (ROS) in various tissues, such as the heart, vasculature, neurons, eyes, and kidneys. We employed a comprehensive approach, integrating both ligand- and structure-based virtual screening followed by experimental validation. Initially, candidate compounds were extracted from extensive drug and chemical libraries using the DeepChem's GraphConvMol algorithm, leveraging its capacity for robust molecular feature representation...

BACKGROUND: In recent years, a significant shift toward remote work, virtual education, and social distancing measures was witnessed, thereby leading people to increasingly depend on digital devices for communication, work, and entertainment. This increased exposure to screens has raised concerns regarding its potential impact on cognitive function. PURPOSE: This study investigated the relationship between screen time and cognitive function among healthy young adults...

S-Adenosyl-l-homocysteine hydrolase (SAHH) is a crucial enzyme that governs S-adenosyl methionine (SAM)-dependent methylation reactions within cells and regulates the intracellular concentration of SAH. Legionella pneumophila, the causative pathogen of Legionnaires' disease, encodes Lpg2021, which is the first identified dimeric SAHH in bacteria and is a promising target for drug development. Here, we report the structure of Lpg2021 in its ligand-free state and in complexes with adenine (ADE), adenosine (ADO), and 3-Deazaneplanocin A (DZNep)...

BACKGROUND: Overall, the potential utility of iVR technology in orthopaedic surgery is promising. The attitudes of medical students and surgical trainees on VR simulated surgical training have been overwhelmingly positive. However, further research and understanding of the attitudes of practicing orthopaedic surgeons and Fellows are needed to appreciate its benefits for clinical practice. PURPOSE: The purpose of this study was to assess the attitudes of Canadian orthopaedic surgeons and Fellows on the value of iVR for surgical training, clinical practice, and distance learning...

Understanding mechanisms of allosteric regulation remains elusive for the SARS-CoV-2 spike protein, despite the increasing interest and effort in discovering allosteric inhibitors of the viral activity and interactions with the host receptor ACE2. The challenges of discovering allosteric modulators of the SARS-CoV-2 spike proteins are associated with the diversity of cryptic allosteric sites and complex molecular mechanisms that can be employed by allosteric ligands, including the alteration of the conformational equilibrium of spike protein and preferential stabilization of specific functional states...