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Neurodegenerative diseases (NDDs) are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells in the central nervous system (CNS). Identification of viable therapeutic targets and new treatments for CNS disorders and in particular, for NDDs is a major challenge in the field of drug discovery. These...
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Context 1
... compounds resulting from HTS screens-the so-called "hits"-are the prototypes from which drug "leads" are ultimately formed through additional combinatorial and medicinal chemistry. Following the screening of several hundred thousand small-molecules, a few hundred "hits" may be identified, leading potentially to viable drug compounds ( Figure 1). Potential hits from the HTS must then be configured for delivery, metabolism, and pharmacokinetics to suggest initial lead compounds. ...
Context 2
... compounds resulting from HTS screens-the so-called "hits"-are the prototypes from which drug "leads" are ultimately formed through additional combinatorial and medicinal chemistry. Following the screening of several hundred thousand small-molecules, a few hundred "hits" may be identified, leading potentially to viable drug compounds ( Figure 1). Potential hits from the HTS must then be configured for delivery, metabolism, and pharmacokinetics to suggest initial lead compounds. ...
Citations
... It is interesting to note that this technique can aid in the optimization of potential drugs, leading to their approvals being granted. Instances of some licensed drugs that were optimized using CADD are captopril, dorzolamide, oseltamivir, aliskiren, and nolatrexed [13,17,18]. ...
Acute myeloid leukemia (AML) takes center stage as a highly prevalent and aggressive clonal disorder affecting hematological stem cells. FMS-like tyrosine kinase 3 (FLT3) mutations were prevalent in nearly 30% of the AML cases. However, efforts have led to the development of anti-mutant FLT3 drugs, such as midostaurin, gilteritinib, and quizartinib, to improve treatments. Currently, we are exploring the ability of compounds from anti-leukemic plants to be used in AML therapies, focusing on mutant FLT3 inhibition. Employing computational techniques such as drug-likeness assessment, molecular docking, pharmacokinetics properties profiling, molecular dynamics simulations (MDS), and free energy calculations, we identified 43 out of 57 compounds with oral drug potential. Notably, 7 out of 43 compounds, including flavopiridol, sanggenol Q, norwogonin, oblongixanthones A, oblongixanthones B, apigenin, and luteolin exhibited strong binding affinities ranging from −9.0 to −9.8 kcal/mol, surpassing the control drug gilteritinib (−6.3 kcal/mol). Notably, flavopiridol and norwogonin displayed highly favorable pharmacokinetics and low toxicity profiles. MDS confirmed the stability of their binding through parameters such as root mean square deviation, root mean square fluctuation, and radius of gyration (R g) over 100 ns simulations. Flavopiridol and norwogonin emerge as promising candidates for the development of mutant FLT3 inhibitors. Therefore, experimental studies are warranted to validate their therapeutic potential.
... Another key advantage virtual screening is its ability to scan huge libraries, which is not feasible in standard high-throughput screening (HTS) limited to hundreds of thousands of molecules. Advancement of synthetic chemistry methodologies and automation have led to the generation of huge virtual libraries, such as Enamine REAL Space [6], consisting of 40 billion different potential molecules, which is 5 orders of magnitude larger than the size of most HTS screening decks [7]. ...
Recent successes in virtual screening have been made possible by large models and extensive chemical libraries. However, combining these elements is challenging: the larger the model, the more expensive it is to run, making ultra-large libraries unfeasible. To address this, we developed a target-agnostic, efficacy-based molecule search model, which allows us to find structurally dissimilar molecules with similar biological activities. We used the best practices to design fast retrieval system, based on processor-optimized SIMD instructions, enabling us to screen the ultra-large 40B Enamine REAL library with 100\% recall rate. We extensively benchmarked our model and several state-of-the-art models for both speed performance and retrieval quality of novel molecules.
... However, there have been notable strides in utilizing high-throughput screening and computer-aided drug design. Aldewachi et al. (2021) comprehensively reviewed these advancements, which offer a fresh perspective that could facilitate the validation of AQP targets in forthcoming research endeavors [189]. ...
... However, there have been notable strides in utilizing high-throughput screening and computer-aided drug design. Aldewachi et al. (2021) comprehensively reviewed these advancements, which offer a fresh perspective that could facilitate the validation of AQP targets in forthcoming research endeavors [189]. ...
Aquaporins (AQPs) are ubiquitous channel proteins that play a critical role in the homeostasis of the cellular environment by allowing the transit of water, chemicals, and ions. They can be found in many different types of cells and organs, including the lungs, eyes, brain, glands, and blood vessels. By controlling the osmotic water flux in processes like cell growth, energy metabolism, migration, adhesion, and proliferation, AQPs are capable of exerting their regulatory influence over a wide range of cellular processes. Tumour cells of varying sources express AQPs significantly, especially in malignant tumours with a high propensity for metastasis. New insights into the roles of AQPs in cell migration and proliferation reinforce the notion that AQPs are crucial players in tumour biology. AQPs have recently been shown to be a powerful tool in the fight against pathogenic antibodies and metastatic cell migration, despite the fact that the molecular processes of aquaporins in pathology are not entirely established. In this review, we shall discuss the several ways in which AQPs are expressed in the body, the unique roles they play in tumorigenesis, and the novel therapeutic approaches that could be adopted to treat carcinoma.
... Traditional high-throughput screening (HTS) has been used for decades as a rapid and cost-effective method to screen several hundred thousand compounds against new targets for lead identification [23]. ...
... These platforms, particularly those that facilitate advanced imaging techniques such as transmission electron microscopy (TEM) and expansion microscopy, offer the opportunity for real-time observation of alterations in aquaporin (AQP) dynamics [260,261]. Finally, high-throughput screening and computer-aided drug design [262,263] could be applied to support AQP target validation in future studies. ...
Neurological disorders are a major group of non-communicable diseases affecting quality of life. Non-Coding RNAs (ncRNAs) have an important role in the etiology of neurological disorders. In studies on the genesis of neurological diseases, aquaporin 4 (AQP4) expression and activity have both been linked to ncRNAs. The upregulation or downregulation of several ncRNAs leads to neurological disorder progression by targeting AQP4. The role of ncRNAs and AQP4 in neurological disorders is discussed in this review.
... This involves high-throughput screening of thousands to millions of compounds to identify potential drug candidates. The compounds that show promise then go through various phases of preclinical and clinical testing to assess their safety and efficacy, including optimization of hit compounds for in vitro potency, ADME, toxicity, and in vivo efficacy [4,5]. ...
... High-throughput screening (HTS) assays are powerful techniques used in drug discovery and chemical biology to rapidly test large compound libraries against biological targets or cellular systems. HTS assays enable the screening of thousands to millions of compounds in a relatively short period, providing valuable information about their activity, potency, and selectivity [197]. ...
The biodegradation of diverse organic compounds plays a pivotal role in environmental sustainability and waste management. In recent years, genetically engineered microbial cells have emerged as a promising tool to enhance biodegradation capabilities. This study presents an innovative approach to produce amino acids and nucleic acids by manipulating microbial genomes, shedding light on their relevance to biodegradation. Through the power of genetic engineering, microbial cells can be harnessed to efficiently degrade a wide range of pollutants, contributing to a cleaner and healthier environment. This study explores the transformative potential of genetic engineering in unlocking the biodegradative capacity of microbial cells and highlights its significance in the production of amino acids and nucleic acids. By leveraging these advancements, we can pave the way towards sustainable waste management and environmental remediation, ensuring a greener and more sustainable future.
... To search for new chemical entities, high throughput screen (HTS) methods are often used to screen millions of compounds rapidly [40]. Despite that, this conventional drug discovery approach remains expensive for academic laboratories [41]. ...
The rampant spread of multidrug-resistant Pseudomonas aeruginosa strains severely threatens global health. This severity is compounded against the backdrop of a stagnating antibiotics development pipeline. Moreover, with many promising therapeutics falling short of expectations in clinical trials, targeting the las quorum sensing (QS) system remains an attractive therapeutic strategy to combat P. aeruginosa infection. Thus, our primary goal was to develop a drug prediction algorithm using machine learning to identify potent LasR inhibitors. In this work, we demonstrated using a Multilayer Perceptron (MLP) algorithm boosted with AdaBoostM1 to discriminate between active and inactive LasR inhibitors. The optimal model performance was evaluated using 5-fold cross-validation and test sets. Our best model achieved a 90.7% accuracy in distinguishing active from inactive LasR inhibitors, an area under the Receiver Operating Characteristic Curve value of 0.95, and a Matthews correlation coefficient value of 0.81 when evaluated using test sets. Subsequently, we deployed the model against the Enamine database. The top-ranked compounds were further evaluated for their target engagement activity using molecular docking studies, Molecular Dynamics simulations, MM-GBSA analysis, and Free Energy Landscape analysis. Our data indicate that several of our chosen top hits showed better ligand-binding affinities than naringenin, a competitive LasR inhibitor. Among the six top hits, five of these compounds were predicted to be LasR inhibitors that could be used to treat P. aeruginosa-associated infections. To our knowledge, this study provides the first assessment of using an MLP-based QSAR model for discovering potent LasR inhibitors to attenuate P. aeruginosa infections.
... the diffusion of artemisinin and act partner-drug resistant parasites drives an urgent investigation for novel therapies, especially cerebral malaria. computer-aided drug design (caDD) and highthroughput screening (HtS) are the two most promising methods for developing novel treatments and could meet the urgent demand for treatment of malaria and should be used in the pharmaceutical industry [35][36]. ...
Objective
Microscopy was used to characterize platelet-Plasmodium-infected erythrocyte interactions in patients infected with Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale or Plasmodium malariae, and to investigate the relationship between platelet-associated parasite killing and parasite clearance.
Methods
Data from 244 malaria patients admitted to the Fourth People’s Hospital of Nanning between 1 January 2011 and 30 September 2022, and 45 healthy controls, were collected prospectively and assessed retrospectively. Characteristics of platelet–erythrocyte interactions were visualized by microscopy, and blood cell count and clinical profiles of these participants were obtained from the electronic medical records. ANOVA, contingency tables and Cox proportional hazards regression models were used to do statistical analysis on the subgroups.
Results
Platelet enlargement and minor pseudopodia development were observed. Platelets were found directly attaching to parasitized erythrocytes by all Plasmodium species studied, especially mature stages, and lysis of parasitized erythrocytes was connected to platelet-mediated cytolysis. Platelet counts were correlated inversely with parasitaemia and duration of parasite clearance. Artemisinin combination therapy was more effective than artemisinin alone in clearing Plasmodium in patients with thrombocytopenia.
Conclusions
Platelet-parasitized erythrocytes cell-to-cell contacts initiated platelet-associated parasite killing and helped to limit Plasmodium infection in cases of human malaria. The weakening platelet-associated parasite killing effects could be counteracted by artemisinin combination therapy in patients with thrombocytopenia.
... Inhibitors of ADAM10 and 17 in the present study indicated that small-molecule drugs may serve as a novel therapeutic option for NB; however, the development of therapeutic methods for clinical needs is still an urgent problem that remains to be solved. Computer-aided drug design tools (56) and High-Throughput Screening (57) platforms are required to develop new drugs. AQPs are required for MMP-dependent migration of cancer cells. ...
T cell-based immunotherapy has achieved remarkable beneficial clinical outcomes. Tumor-derived NKG2D ligands (NKG2DL) allow tumors to escape immunologic surveillance. However, the mechanism underlying NKG2DL-mediated immune escape in neuroblastoma (NB) remains incompletely understood. In the present study, first soluble NKG2DL, soluble major histocompatibility complex (MHC) class-I-related chain A and soluble UL-16 binding proteins expression levels were determined in both the serum from patients with NB and in NB cell line culture supernatants. NB cell-derived sNKG2DL was initially cleaved by ADAM10 and ADAM17. Furthermore, sNKG2DL expression levels were positively correlated with the immunosuppressive microenvironment and poor prognosis. Tumor-derived sNKG2DL induced degradation of NKG2D on CD8+ T cells and impaired CD8+ T cell proliferation, IFN-γ production, and CD107a translocation. More importantly, blockage of sNKG2DL increased the antitumor activity of CD8+ T cells. Thus, the results showed that NB-induced immunosuppression was achieved through tumor-derived sMICA and sULBP-2, and blockage of the tumor-derived sNKG2DLs with sNKG2DL neutralizing antibodies was a novel strategy to recover T-cell function and enhance antitumor immunotherapy.
