Identification of Differentially Expressed mRNAs and lncRNAs Contributes to Elucidation of Underlying Pathogenesis and Therapeutic Strategy of Recurrent Implantation Failure.

Recurrent implantation failure (RIF) is a complex and poorly understood clinical disorder characterized by failure to conceive after repeated embryo transfers. Endometrial receptivity (ER) is a prerequisite for implantation, and ER disorders are associated with RIF. However, little is known regarding the molecular mechanisms underlying ER in RIF. In the present study, RNA sequencing data from the mid-secretory endometrium of patients with and without RIF were analyzed to explore the potential long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) involved in RIF. The analysis revealed 213 and 1485 differentially expressed mRNAs and lncRNAs, respectively (fold change ≥ 2 and p < 0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these genes were mostly involved in processes related to immunity or inflammation. 5 key genes (TTR, ALB, TF, AFP, and CFTR) and a key module including 14 hub genes (AFP, ALB, APOA1, APOA2, APOB, APOH, FABP1, FGA, FGG, GC, ITIH2, SERPIND1, TF and TTR) were identified in the protein-protein interaction (PPI) network. The 5 key genes were used to further explore the lncRNA-miRNA-mRNA regulatory network. Finally, the drug ML-193 based on the 14 hub genes was identifed through the CMap. After ML-193 treatment, endometrial cell proliferation was increased, the hub genes were mostly down-regulated, and the ER marker HOXA10 was up-regulated. These results offer insights into the regulatory mechanisms of lncRNAs and mRNAs and suggest ML-193 as a therapeutic agent for RIF by enhancing ER.

Artificial intelligence innovations in neurosurgical oncology: a narrative review.

PURPOSE: Artificial Intelligence (AI) has become increasingly integrated clinically within neurosurgical oncology. This report reviews the cutting-edge technologies impacting tumor treatment and outcomes. METHODS: A rigorous literature search was performed with the aid of a research librarian to identify key articles referencing AI and related topics (machine learning (ML), computer vision (CV), augmented reality (AR), virtual reality (VR), etc.) for neurosurgical care of brain or spinal tumors. RESULTS: Treatment of central nervous system (CNS) tumors is being improved through advances across AI-such as AL, CV, and AR/VR. AI aided diagnostic and prognostication tools can influence pre-operative patient experience, while automated tumor segmentation and total resection predictions aid surgical planning. Novel intra-operative tools can rapidly provide histopathologic tumor classification to streamline treatment strategies. Post-operative video analysis, paired with rich surgical simulations, can enhance training feedback and regimens. CONCLUSION: While limited generalizability, bias, and patient data security are current concerns, the advent of federated learning, along with growing data consortiums, provides an avenue for increasingly safe, powerful, and effective AI platforms in the future.

PlasmidHunter: accurate and fast prediction of plasmid sequences using gene content profile and machine learning.

Plasmids are extrachromosomal DNA found in microorganisms. They often carry beneficial genes that help bacteria adapt to harsh conditions. Plasmids are also important tools in genetic engineering, gene therapy, and drug production. However, it can be difficult to identify plasmid sequences from chromosomal sequences in genomic and metagenomic data. Here, we have developed a new tool called PlasmidHunter, which uses machine learning to predict plasmid sequences based on gene content profile. PlasmidHunter can achieve high accuracies (up to 97.6%) and high speeds in benchmark tests including both simulated contigs and real metagenomic plasmidome data, outperforming other existing tools.

Predicting tablet properties using In-Line measurements and evolutionary equation Discovery: A high shear wet granulation study.

High shear wet granulation (HSWG) is widely used in tablet manufacturing mainly because of its advantages in improving flowability, powder handling, process run time, size distribution, and preventing segregation. In line process analytical technology measurements are essential in capturing detailed particle dynamics and presenting real-time data to uncover the complexity of the HSWG process and ultimately for process control. This study presents an opportunity to predict the properties of the granules and tablets through torque measurement of the granulation bowl and the force exerted on a novel force probe within the powder bed. Inline force measurements are found to be more sensitive than torque measurements to the granulation process. The characteristic force profiles present the overall fingerprint of the high shear wet granulation, in which the evolution of the granule formation can improve our understanding of the granulation process. This provides rich information relating to the properties of the granules, identification of the even distribution of the binder liquid, and potential granulation end point. Data were obtained from an experimental high shear mixer across a range of key process parameters using a face-centred surface response design of experiment (DoE). A closed-form analytical model was developed from the DOE matrix using the discovery of evolutionary equations. The model is able to provide a strong predictive indication of the expected tablet tensile strength based only on the data in-line. The use of a closed form mathematical equation carries notable advantages over other AI methodologies such as artificial neural networks, notably improved interpretability/interrogability, and minimal inference costs, thus allowing the model to be used for real-time decision making and process control. The capability of accurately predicting, in real time, the required compaction force required to achieve the desired tablet tensile strength from upstream data carries the potential to ensure compression machine settings rapidly reach and are maintained at optimal values, thus maximising efficiency and minimising waste.

Machine learning-based diagnosis and prognosis of IgAN: A systematic review and meta-analysis.

Purpose: Plenty of studies have explored the diagnosis and prognosis of IgA nephropathy (IgAN) based on machine learning (ML), but the accuracy lacks the support of evidence-based medical evidence. We aim at this problem to guide the precision treatment of IgAN. Methods: Embase, Pubmed, Cochrane Library, and Web of Science were searched systematically until February 24th, 2024, for publications on ML-based diagnosis and prognosis of IgAN. Subgroup analysis or meta-regression was conducted according to modeling method, follow-up time, endpoint definition, and variable type. Further, the rank sum test was applied to compare the discrimination ability of prognosis. Results: A total of 47 studies involving 51,935 patients were eligible. Among the 38 diagnostic models, the pooled C-index was 0.902 (95 % CI: 0.878-0.926) in 27 diagnostic models. Of the 162 prognostic models, the C-index for model discrimination of 144 prognostic models was 0.838 (95 % CI: 0.827-0.850) in training. The overall discrimination ability of prognosis was as follows: COX regression > new ML models (e.g. ANN, DT, RF, SVM, XGBoost) > traditional ML models (logistic regression) > Naïve Bayesian network (P < 0.05). External validation of IIgAN-RPT in 19 models showed a pooled C-index of 0.801 (95 % CI: 0.784-0.817). Conclusions: New ML models have shown application values that are as good as traditional ML models, both in diagnosis and prognosis. In addition, future models are desired to use a more sensitive prognostic endpoint (albuminuria), improve predictive ability in moderate progression risk, and ultimately translate into clinically applicable intelligent tools.

Corn leaf disease: insightful diagnosis using VGG16 empowered by explainable AI.

The agricultural sector is pivotal to food security and economic stability worldwide. Corn holds particular significance in the global food industry, especially in developing countries where agriculture is a cornerstone of the economy. However, corn crops are vulnerable to various diseases that can significantly reduce yields. Early detection and precise classification of these diseases are crucial to prevent damage and ensure high crop productivity. This study leverages the VGG16 deep learning (DL) model to classify corn leaves into four categories: healthy, blight, gray spot, and common rust. Despite the efficacy of DL models, they often face challenges related to the explainability of their decision-making processes. To address this, Layer-wise Relevance Propagation (LRP) is employed to enhance the model's transparency by generating intuitive and human-readable heat maps of input images. The proposed VGG16 model, augmented with LRP, outperformed previous state-of-the-art models in classifying corn leaf diseases. Simulation results demonstrated that the model not only achieved high accuracy but also provided interpretable results, highlighting critical regions in the images used for classification. By generating human-readable explanations, this approach ensures greater transparency and reliability in model performance, aiding farmers in improving their crop yields.

Knowledge, attitude, and practice of artificial intelligence among medical students in Sudan: a cross-sectional study.

Introduction: In this cross-sectional study, the authors explored the knowledge, attitudes, and practices related to artificial intelligence (AI) among medical students in Sudan. With AI increasingly impacting healthcare, understanding its integration into medical education is crucial. This study aimed to assess the current state of AI awareness, perceptions, and practical experiences among medical students in Sudan. The authors aimed to evaluate the extent of AI familiarity among Sudanese medical students by examining their attitudes toward its application in medicine. Additionally, this study seeks to identify the factors influencing knowledge levels and explore the practical implementation of AI in the medical field. Method: A web-based survey was distributed to medical students in Sudan via social media platforms and e-mail during October 2023. The survey included questions on demographic information, knowledge of AI, attitudes toward its applications, and practical experiences. The descriptive statistics, χ2 tests, logistic regression, and correlations were analyzed using SPSS version 26.0. Results: Out of the 762 participants, the majority exhibited a basic understanding of AI, but detailed knowledge of its applications was limited. Positive attitudes toward the importance of AI in diagnosis, radiology, and pathology were prevalent. However, practical application of these methods was infrequent, with only a minority of the participants having hands-on experience. Factors influencing knowledge included the lack of a formal curriculum and gender disparities. Conclusion: This study highlights the need for comprehensive AI education in medical training programs in Sudan. While participants displayed positive attitudes, there was a notable gap in practical experience. Addressing these gaps through targeted educational interventions is crucial for preparing future healthcare professionals to navigate the evolving landscape of AI in medicine. Recommendations: Policy efforts should focus on integrating AI education into the medical curriculum to ensure readiness for the technological advancements shaping the future of healthcare.

A machine learning clinic scoring system for hepatocellular carcinoma based on the Surveillance, Epidemiology, and End Results database.

Background: Hepatocellular carcinoma (HCC) poses a global threat to life; however, numerical tools to predict the clinical prognosis of these patients remain scarce. The primary objective of this study is to establish a clinical scoring system for evaluating the overall survival (OS) rate and cancer-specific survival (CSS) rate in HCC patients. Methods: From the Surveillance, Epidemiology, and End Results (SEER) Program, we identified 45,827 primary HCC patients. These cases were randomly allocated to a training cohort (22,914 patients) and a validation cohort (22,913 patients). Univariate and multivariate Cox regression analyses, coupled with Kaplan-Meier methods, were employed to evaluate prognosis-related clinical and demographic features. Factors demonstrating prognostic significance were used to construct the model. The model's stability and accuracy were assessed through C-index, receiver operating characteristic (ROC) curves, calibration curves, and clinical decision curve analysis (DCA), while comparisons were made with the American Joint Committee on Cancer (AJCC) staging. Ultimately, machine learning (ML) quantified the variables in the model to establish a clinical scoring system. Results: Univariate and multivariate Cox regression analyses identified 11 demographic and clinical-pathological features as independent prognostic indicators for both CSS and OS using. Two models, each incorporating the 11 features, were developed, both of which demonstrated significant prognostic relevance. The C-index for predicting CSS and OS surpassed that of the AJCC staging system. The area under the curve (AUC) in time-dependent ROC consistently exceeded 0.74 in both the training and validation sets. Furthermore, internal and external calibration plots indicated that the model predictions aligned closely with observed outcomes. Additionally, DCA demonstrated the superiority of the model over the AJCC staging system, yielding greater clinical net benefit. Ultimately, the quantified clinical scoring system could efficiently discriminate between high and low-risk patients. Conclusions: A ML clinical scoring system trained on a large-scale dataset exhibits good predictive and risk stratification performance in the cohorts. Such a clinical scoring system is readily integrable into clinical practice and will be valuable in enhancing the accuracy and efficiency of HCC management.

Early diagnosis of HIV cases by means of text mining and machine learning models on clinical notes.

Undiagnosed and untreated human immunodeficiency virus (HIV) infection increases morbidity in the HIV-positive person and allows onward transmission of the virus. Minimizing missed opportunities for HIV diagnosis when a patient visits a healthcare facility is essential in restraining the epidemic and working toward its eventual elimination. Most state-of-the-art proposals employ machine learning (ML) methods and structured data to enhance HIV diagnoses, however, there is a dearth of recent proposals utilizing unstructured textual data from Electronic Health Records (EHRs). In this work, we propose to use only the unstructured text of the clinical notes as evidence for the classification of patients as suspected or not suspected. For this purpose, we first compile a dataset of real clinical notes from a hospital with patients classified as suspects and non-suspects of having HIV. Then, we evaluate the effectiveness of two types of classification models to identify patients suspected of being infected with the virus: classical ML algorithms and two Large Language Models (LLMs) from the biomedical domain in Spanish. The results show that both LLMs outperform classical ML algorithms in the two settings we explore: one dataset version is balanced, containing an equal number of suspicious and non-suspicious patients, while the other reflects the real distribution of patients in the hospital, being unbalanced. We obtain F1 score figures of 94.7 with both LLMs in the unbalanced setting, while in the balance one, RoBERTaBio model outperforms the other one with a F1 score of 95.7. The findings indicate that leveraging unstructured text with LLMs in the biomedical domain yields promising outcomes in diminishing missed opportunities for HIV diagnosis. A tool based on our system could assist a doctor in deciding whether a patient in consultation should undergo a serological test.

Machine learning approach to predict venous thromboembolism among patients undergoing multi-level spinal posterior instrumented fusion.

Background: The absence of consensus for prophylaxis of venous thromboembolism (VTE) in spine surgery underscores the importance of identifying patients at risk. This study incorporated machine learning (ML) models to assess key risk factors of VTE in patients who underwent posterior spinal instrumented fusion. Methods: Data was collected from the IBM MarketScan Database [2009-2021] for patients ≥18 years old who underwent spinal posterior instrumentation (3-6 levels), excluding traumas, malignancies, and infections. VTE incidence (deep vein thrombosis and pulmonary embolism) was recorded 90-day post-surgery. Risk factors for VTE were investigated and compared through several ML models including logistic regression, linear support vector machine (LSVM), random forest, XGBoost, and neural networks. Results: Among the 141,697 patients who underwent spinal fusion with posterior instrumentation (3-6 levels), the overall 90-day VTE rate was 3.81%. The LSVM model demonstrated the best prediction with an area under the curve (AUC) of 0.68. The most important features for prediction of VTE included remote history of VTE, diagnosis of chronic hypercoagulability, metastatic cancer, hemiplegia, and chronic renal disease. Patients who did not have these five key risk factors had a 90-day VTE rate of 2.95%. Patients who had an increasing number of key risk factors had subsequently higher risks of postoperative VTE. Conclusions: The analysis of the data with different ML models identified 5 key variables that are most closely associated with VTE. Using these variables, we have developed a simple risk model with additive odds ratio ranging from 2.80 (1 risk factor) to 46.92 (4 risk factors) over 90 days after posterior spinal fusion surgery. These findings can help surgeons risk-stratify their patients for VTE risk, and potentially guide subsequent chemoprophylaxis.

Clinical prediction for surgical versus nonsurgical interventions in patients with vertebral osteomyelitis and discitis.

Background: Vertebral osteomyelitis and discitis (VOD), an infection of intervertebral discs, often requires spine surgical intervention and timely management to prevent adverse outcomes. Our study aims to develop a machine learning (ML) model to predict the indication for surgical intervention (during the same hospital stay) versus nonsurgical management in patients with VOD. Methods: This retrospective study included adult patients (≥18 years) with VOD (ICD-10 diagnosis codes M46.2,3,4,5) treated at a single institution between 01/01/2015 and 12/31/2019. The primary outcome studied was surgery. Candidate predictors were age, sex, race, Elixhauser comorbidity index, first-recorded lab values, first-recorded vital signs, and admit diagnosis. After splitting the dataset, XGBoost, logistic regression, and K-neighbor classifier algorithms were trained and tested for model development. Results: A total of 1,111 patients were included in this study, among which 30% (n=339) of patients underwent surgical intervention. Age and sex did not significantly differ between the two groups; however, race did significantly differ (P<0.0001), with the surgical group having a higher percentage of white patients. The top ten model features for the best-performing model (XGBoost) were as follows (in descending order of importance): admit diagnosis of fever, negative culture, Staphylococcus aureus culture, partial pressure of arterial oxygen to fractional inspired oxygen ratio (PaO2:FiO2), admit diagnosis of intraspinal abscess and granuloma, admit diagnosis of sepsis, race, troponin I, acid-fast bacillus culture, and alveolar-arterial gradient (A-a gradient). XGBoost model metrics were as follows: accuracy =0.7534, sensitivity =0.7436, specificity =0.7586, and area under the curve (AUC) =0.8210. Conclusions: The XGBoost model reliably predicts the indication for surgical intervention based on several readily available patient demographic information and clinical features. The interpretability of a supervised ML model provides robust insight into patient outcomes. Furthermore, it paves the way for the development of an efficient hospital resource allocation instrument, designed to guide clinical suggestions.

A Comparison of Machine Learning Approaches for predicting Hepatotoxicity potential using Chemical Structure and Targeted Transcriptomic Data.

Animal toxicity testing is time and resource intensive, making it difficult to keep pace with the number of substances requiring assessment. Machine learning (ML) models that use chemical structure information and high-throughput experimental data can be helpful in predicting potential toxicity . However, much of the toxicity data used to train ML models is biased with an unequal balance of positives and negatives primarily since substances selected for in vivo testing are expected to elicit some toxicity effect. To investigate the impact this bias had on predictive performance, various sampling approaches were used to balance in vivo toxicity data as part of a supervised ML workflow to predict hepatotoxicity outcomes from chemical structure and/or targeted transcriptomic data. From the chronic, subchronic, developmental, multigenerational reproductive, and subacute repeat-dose testing toxicity outcomes with a minimum of 50 positive and 50 negative substances, 18 different study-toxicity outcome combinations were evaluated in up to 7 ML models. These included Artificial Neural Networks, Random Forests, Bernouilli Naïve Bayes, Gradient Boosting, and Support Vector classification algorithms which were compared with a local approach, Generalised Read-Across (GenRA), a similarity-weighted k-Nearest Neighbour (k-NN) method. The mean CV F1 performance for unbalanced data across all classifiers and descriptors for chronic liver effects was 0.735 (0.0395 SD). Mean CV F1 performance dropped to 0.639 (0.073 SD) with over-sampling approaches though the poorer performance of KNN approaches in some cases contributed to the observed decrease (mean CV F1 performance excluding KNN was 0.697 (0.072 SD)). With under-sampling approaches, the mean CV F1 was 0.523 (0.083 SD). For developmental liver effects, the mean CV F1 performance was much lower with 0.089 (0.111 SD) for unbalanced approaches and 0.149 (0.084 SD) for under-sampling. Over-sampling approaches led to an increase in mean CV F1 performance (0.234, (0.107 SD)) for developmental liver toxicity. Model performance was found to be dependent on dataset, model type, balancing approach and feature selection. Accordingly tailoring ML workflows for predicting toxicity should consider class imbalance and rely on simpler classifiers first.

Molecular Docking of Intrinsically Disordered Proteins: Challenges and Strategies.

Intrinsically disordered proteins (IDPs) are a novel class of proteins that have established a significant importance and attention within a very short period of time. These proteins are essentially characterized by their inherent structural disorder, encoded mainly by their amino acid sequences. The profound abundance of IDPs and intrinsically disordered regions (IDRs) in the biological world delineates their deep-rooted functionality. IDPs and IDRs convey such extensive functionality through their unique dynamic nature, which enables them to carry out huge number of multifaceted biomolecular interactions and make them "interaction hub" of the cellular systems. Additionally, with such widespread functions, their misfunctioning is also intimately associated with multiple diseases. Thus, understanding the dynamic heterogeneity of various IDPs along with their interactions with respective binding partners is an important field with immense potentials in biomolecular research. In this context, molecular docking-based computational approaches have proven to be remarkable in case of ordered proteins. Molecular docking methods essentially model the biomolecular interactions in both structural and energetic terms and use this information to characterize the putative interactions between the two participant molecules. However, direct applications of the conventional docking methods to study IDPs are largely limited by their structural heterogeneity and demands for unique IDP-centric strategies. Thus, in this chapter, we have presented an overview of current methodologies for successful docking operations involving IDPs and IDRs. These specialized methods majorly include the ensemble-based and fragment-based approaches with their own benefits and limitations. More recently, artificial intelligence and machine learning-assisted approaches are also used to significantly reduce the complexity and computational burden associated with various docking applications. Thus, this chapter aims to provide a comprehensive summary of major challenges and recent advancements of molecular docking approaches in the IDP field for their better utilization and greater applicability.Asp (D).

Traffic Feature Selection and Distributed Denial of Service Attack Detection in Software-Defined Networks Based on Machine Learning.

As 5G technology becomes more widespread, the significant improvement in network speed and connection density has introduced more challenges to network security. In particular, distributed denial of service (DDoS) attacks have become more frequent and complex in software-defined network (SDN) environments. The complexity and diversity of 5G networks result in a great deal of unnecessary features, which may introduce noise into the detection process of an intrusion detection system (IDS) and reduce the generalization ability of the model. This paper aims to improve the performance of the IDS in 5G networks, especially in terms of detection speed and accuracy. It proposes an innovative feature selection (FS) method to filter out the most representative and distinguishing features from network traffic data to improve the robustness and detection efficiency of the IDS. To confirm the suggested method's efficacy, this paper uses four common machine learning (ML) models to evaluate the InSDN, CICIDS2017, and CICIDS2018 datasets and conducts real-time DDoS attack detection on the simulation platform. According to experimental results, the suggested FS technique may match 5G network requirements for high speed and high reliability of the IDS while also drastically cutting down on detection time and preserving or improving DDoS detection accuracy.

An Advanced Lung Carcinoma Prediction and Risk Screening Model Using Transfer Learning.

Lung cancer, also known as lung carcinoma, has a high death rate, but an early diagnosis can substantially reduce this risk. In the current era, prediction models face challenges such as low accuracy, excessive noise, and low contrast. To resolve these problems, an advanced lung carcinoma prediction and risk screening model using transfer learning is proposed. Our proposed model initially preprocesses lung computed tomography images for noise removal, contrast stretching, convex hull lung region extraction, and edge enhancement. The next phase segments the preprocessed images using the modified Bates distribution coati optimization (B-RGS) algorithm to extract key features. The PResNet classifier then categorizes the cancer as normal or abnormal. For abnormal cases, further risk screening determines whether the risk is low or high. Experimental results depict that our proposed model performs at levels similar to other state-of-the-art models, achieving enhanced accuracy, precision, and recall rates of 98.21%, 98.71%, and 97.46%, respectively. These results validate the efficiency and effectiveness of our suggested methodology in early lung carcinoma prediction and risk assessment.

Evolving and Novel Applications of Artificial Intelligence in Thoracic Imaging.

The advent of artificial intelligence (AI) is revolutionizing medicine, particularly radiology. With the development of newer models, AI applications are demonstrating improved performance and versatile utility in the clinical setting. Thoracic imaging is an area of profound interest, given the prevalence of chest imaging and the significant health implications of thoracic diseases. This review aims to highlight the promising applications of AI within thoracic imaging. It examines the role of AI, including its contributions to improving diagnostic evaluation and interpretation, enhancing workflow, and aiding in invasive procedures. Next, it further highlights the current challenges and limitations faced by AI, such as the necessity of 'big data', ethical and legal considerations, and bias in representation. Lastly, it explores the potential directions for the application of AI in thoracic radiology.

UBA2 SUMOylates NQO1 and promotes the proliferation of hepatocellular carcinoma by modulating the MAPK pathway.

In our previous study, we found that small ubiquitin-related modifier (SUMO)-activating enzyme ubiquitin-associated-2 domain (UBA2) was upregulated in hepatocellular carcinoma (HCC) patients who were insensitive to chemoembolization. In this study, we aimed to investigate the role of UBA2 in HCC progression. Three cohorts were used to evaluate the efficacy of UBA2 as a prognostic factor for HCC. Our results indicated that UBA2 was associated with aggressive clinical behaviors and was a strong indicator of poor prognosis in HCC. In vitro experiments demonstrated that UBA2 accelerated cell growth, invasion, and migration. These results were further supported by in vivo experiments. RNA-sequencing analysis indicated NQO1 as a target of UBA2, with its levels altering following UBA2 manipulation. The results were verified by western blotting (WB) and quantitative PCR. The SUMOplot Analysis Program predicted lysine residue K240 as a modification target of UBA2, which was confirmed by immunoprecipitation (IP) assays. Subsequent mutation of NQO1 at K240 in HCC cell lines and functional assays revealed the significance of this modification. In addition, the oncogenic effect of UBA2 could be reversed by the SUMO inhibitor ML792 in vivo and in vitro. In conclusion, our study elucidated the regulatory mechanism of UBA2 in HCC and suggested that the SUMO inhibitor ML792 may be an effective combinatory treatment for patients with aberrant UBA2 expression.

MDFit: automated molecular simulations workflow enables high throughput assessment of ligands-protein dynamics.

Molecular dynamics (MD) simulation is a powerful tool for characterizing ligand-protein conformational dynamics and offers significant advantages over docking and other rigid structure-based computational methods. However, setting up, running, and analyzing MD simulations continues to be a multi-step process making it cumbersome to assess a library of ligands in a protein binding pocket using MD. We present an automated workflow that streamlines setting up, running, and analyzing Desmond MD simulations for protein-ligand complexes using machine learning (ML) models. The workflow takes a library of pre-docked ligands and a prepared protein structure as input, sets up and runs MD with each protein-ligand complex, and generates simulation fingerprints for each ligand. Simulation fingerprints (SimFP) capture protein-ligand compatibility, including stability of different ligand-pocket interactions and other useful metrics that enable easy rank-ordering of the ligand library for pocket optimization. SimFPs from a ligand library are used to build & deploy ML models that predict binding assay outcomes and automatically infer important interactions. Unlike relative free-energy methods that are constrained to assess ligands with high chemical similarity, ML models based on SimFPs can accommodate diverse ligand sets. We present two case studies on how SimFP helps delineate structure-activity relationship (SAR) trends and explain potency differences across matched-molecular pairs of (1) cyclic peptides targeting PD-L1 and (2) small molecule inhibitors targeting CDK9.

Elucidating molecular mechanism and chemical space of chalcones through biological networks and machine learning approaches.

We developed a bio-cheminformatics method, exploring disease inhibition mechanisms using machine learning-enhanced quantitative structure-activity relationship (ML-QSAR) models and knowledge-driven neural networks. ML-QSAR models were developed using molecular fingerprint descriptors and the Random Forest algorithm to explore the chemical spaces of Chalcones inhibitors against diverse disease properties, including antifungal, anti-inflammatory, anticancer, antimicrobial, and antiviral effects. We generated and validated robust machine learning-based bioactivity prediction models (https://github.com/RatulChemoinformatics/QSAR) for the top genes. These models underwent ROC and applicability domain analysis, followed by molecular docking studies to elucidate the molecular mechanisms of the molecules. Through comprehensive neural network analysis, crucial genes such as AKT1, HSP90AA1, SRC, and STAT3 were identified. The PubChem fingerprint-based model revealed key descriptors: PubchemFP521 for AKT1, PubchemFP180 for SRC, PubchemFP633 for HSP90AA1, and PubchemFP145 and PubchemFP338 for STAT3, consistently contributing to bioactivity across targets. Notably, chalcone derivatives demonstrated significant bioactivity against target genes, with compound RA1 displaying a predictive pIC50 value of 5.76 against HSP90AA1 and strong binding affinities across other targets. Compounds RA5 to RA7 also exhibited high binding affinity scores comparable to or exceeding existing drugs. These findings emphasize the importance of knowledge-based neural network-based research for developing effective drugs against diverse disease properties. These interactions warrant further in vitro and in vivo investigations to elucidate their potential in rational drug design. The presented models provide valuable insights for inhibitor design and hold promise for drug development. Future research will prioritize investigating these molecules for mycobacterium tuberculosis, enhancing the comprehension of effectiveness in addressing infectious diseases.