J Mol Graph Model. 2024 Jan 30;128:108721. doi: 10.1016/j.jmgm.2024.108721. Online ahead of print.

ABSTRACT

The identification of protein-ligand interactions plays a pivotal role in elucidating biological processes and discovering potential bioproducts. Harnessing the capabilities of computational methods in drug discovery, we introduce an innovative Inverted Virtual Screening (IVS) pipeline. This pipeline Integrated molecular dynamics and docking analyses to ensure that protein structures are not only energetically favorable but also representative of stable conformations. The primary objective of this pipeline is to automate and streamline the analysis of protein-ligand interactions at both genomic and transcriptomic scales. In the contemporary post-genomic era, high-throughput computational screening for bioproducts, biological systems, and therapeutic drugs has become a cornerstone practice. This approach offers the promise of cost-effectiveness, time efficiency, and optimization of laboratory work. Nevertheless, a notable deficiency persists in the availability of efficient pipelines capable of automating the virtual screening process, seamlessly integrating input and output, and leveraging the full potential of open-source tools. To bridge this critical gap, we have developed a versatile pipeline known as BioProtIS. This tool seamlessly integrates a suite of state-of-the-art tools, including Modeller, AlphaFold, Gromacs, FPOCKET, and AutoDock Vina, thus facilitating the streamlined docking of ligands with an expansive repertoire of proteins sourced from genomes and transcriptomes, and substrates. To assess the pipeline's performance, we employed the transcriptomes of Cereus jamacaru (a cactus species) and Aspisoma lineatum (firefly), along with the genome of Homo sapiens. This integration not only improves the accuracy of ligand-protein interactions by minimizing replicability deviations but also optimizes the discovery process by enabling the simultaneous evaluation of multiple substrates. Furthermore, our pipeline accommodates distinct testing scenarios, such as blind docking or site-specific targeting, which are invaluable in applications ranging from drug repositioning to the exploration of new allosteric binding sites and toxicity assessments. BioProtIS has been designed with modularity at its core. This inherent flexibility empowers users to make custom modifications directly within the source code, tailoring the pipeline to their specific research needs. Moreover, it lays the foundation for seamless integration of diverse docking algorithms in future iterations, promising ongoing advancements in the field of computational biology. This pipeline is available for free distribution and can be download at: https://github.com/BBMDO/BioProtIS.

PMID:38308972 | DOI:10.1016/j.jmgm.2024.108721

Am J Sports Med. 2024 Feb 2:3635465231220855. doi: 10.1177/03635465231220855. Online ahead of print.

ABSTRACT

BACKGROUND: Posttraumatic osteoarthritis (OA) is a common disorder associated with a high socioeconomic burden, particularly in young, physically active, and working patients. Tranexamic acid (TXA) is commonly used in orthopaedic trauma surgery as an antifibrinolytic agent to control excessive bleeding. Previous studies have reported that TXA modulates inflammation and bone cell function, both of which are dysregulated during posttraumatic OA disease progression.

PURPOSE: To evaluate the therapeutic effects of systemic and topical TXA treatment on the progression of posttraumatic OA in the knee of mice.

STUDY DESIGN: Controlled laboratory study.

METHODS: OA was induced via anterior cruciate ligament (ACL) transection on the right knee of female mice. Mice were treated with TXA or vehicle intraperitoneally daily or intra-articularly weekly for 4 weeks, starting on the day of surgery. Articular cartilage degeneration, synovitis, bone erosion, and osteophyte formation were scored histologically. Micro-computed tomography evaluation was conducted to measure the subchondral bone microstructure and osteophyte volume. Cartilage thickness and bone remodeling were assessed histomorphometrically.

RESULTS: Both systemic and topical TXA treatment significantly reduced cartilage degeneration, synovitis, and bone erosion scores and increased the ratio of hyaline to calcified cartilage thickness in posttraumatic OA. Systemic TXA reversed ACL transection-induced subchondral bone loss and osteophyte formation, whereas topical treatment had no effect. Systemic TXA decreased the number and surface area of osteoclasts, whereas those of osteoblasts were not affected. No effect of topical TXA on osteoblast or osteoclast parameters was observed.

CONCLUSION: Both systemic and topical TXA exerted protective effects on the progression of posttraumatic OA. Drug repurposing of TXA may, therefore, be useful for the prevention or treatment of posttraumatic OA, particularly after ACL surgery.

CLINICAL RELEVANCE: TXA might be beneficial in patients with posttraumatic OA of the knee.

PMID:38305280 | DOI:10.1177/03635465231220855

Curr Res Struct Biol. 2024 Jan 17;7:100128. doi: 10.1016/j.crstbi.2024.100128. eCollection 2024.

ABSTRACT

Plasmodium species are causative agents of malaria, a disease that is a serious global health concern. FDA-approved HIV-1 protease inhibitors (HIV-1 PIs) have been reported to be effective in reducing the infection by Plasmodium parasites in the population co-infected with both HIV-1 and malaria. However, the mechanism of HIV-1 PIs in mitigating Plasmodium pathogenesis during malaria/HIV-1 co-infection is not fully understood. In this study we demonstrate that HIV-1 drugs ritonavir (RTV) and lopinavir (LPV) exhibit the highest inhibition activity against plasmepsin II (PMII) and plasmepsin X (PMX) of P. falciparum. Crystal structures of the complexes of PMII with both drugs have been determined. The inhibitors interact with PMII via multiple hydrogen bonding and hydrophobic interactions. The P4 moiety of RTV forms additional interactions compared to LPV and exhibits conformational flexibility in a large S4 pocket of PMII. Our study is also the first to report inhibition of P. falciparum PMX by RTV and the mode of binding of the drug to the PMX active site. Analysis of the crystal structures implies that PMs can accommodate bulkier groups of these inhibitors in their S4 binding pockets. Structurally similar active sites of different vacuolar and non-vacuolar PMs suggest the potential of HIV-1 PIs in targeting these enzymes with differential affinities. Our structural investigations and biochemical data emphasize PMs as crucial targets for repurposing HIV-1 PIs as antimalarial drugs.

PMID:38304146 | PMC:PMC10830516 | DOI:10.1016/j.crstbi.2024.100128

Curr Cancer Drug Targets. 2024 Feb 1. doi: 10.2174/0115680096283086240116093400. Online ahead of print.

ABSTRACT

BACKGROUND: Melanoma is the most common skin tumor worldwide and still lacks effective therapeutic agents in clinical practice. Repurposing of existing drugs for clinical tumor treatment is an attractive and effective strategy. Loperamide is a commonly used anti-diarrheal drug with excellent safety profiles. However, the affection and mechanism of loperamide in melanoma remain unknown. Herein, the potential anti-melanoma effects and mechanism of loperamide were investigated in vitro and in vivo.

METHODS: In the present study, we demonstrated that loperamide possessed a strong inhibition in cell viability and proliferation in melanoma using MTT, colony formation and EUD incorporation assays. Meanwhile, xenograft tumor models were established to investigate the anti-melanoma activity of loperamide in vivo. Moreover, the effects of loperamide on apoptosis in melanoma cells and potential mechanisms were explored by Annexin V-FITC apoptosis detection, cell cycle, mitochondrial membrane potential assay, reactive oxygen species level detection, and apoptosis-correlation proteins analysis. Furthermore, loperamide-suppressed melanoma metastasis was studied by migration and invasion assays. What's more, immunohistochemical and immunofluorescence staining assays were applied to demonstrate the mechanism of loperamide against melanoma in vivo. Finally, we performed the analysis of routine blood and blood biochemical, as well as hematoxylin-eosin (H&E) staining, in order to investigate the safety properties of loperamide.

RESULTS: Loperamide could observably inhibit melanoma cell proliferation in vitro and in vivo. Meanwhile, loperamide induced melanoma cell apoptosis by accumulation of the sub-G1 cells population, enhancement of reactive oxygen species level, depletion of mitochondrial membrane potential, and apoptosis-related protein activation in vitro. Of note, apoptosis-inducing effects were also observed in vivo. Subsequently, loperamide markedly restrained melanoma cell migration and invasion in vitro and in vivo. Ultimately, loperamide was witnessed to have an amicable safety profile.

CONCLUSION: These findings suggested that repurposing of loperamide might have great potential as a novel and safe alternative strategy to cure melanoma via inhibiting proliferation, inducing apoptosis and cell cycle arrest, and suppressing migration and invasion.

PMID:38303527 | DOI:10.2174/0115680096283086240116093400

Expert Rev Proteomics. 2024 Feb 1. doi: 10.1080/14789450.2024.2313073. Online ahead of print.

ABSTRACT

INTRODUCTION: Due to the segmented functions and complexity of the human brain, the characterization of molecular profiles within specific areas such as brain structures and biofluids is essential to unveil the molecular basis for structure specialization as well as the molecular imbalance associated with neurodegenerative and psychiatric diseases.

AREAS COVERED: Much of our knowledge about brain functionality derives from neurophysiological, anatomical, and transcriptomic approaches. More recently, laser capture and imaging proteomics, technological and computational developments in LC-MS/MS, as well as antibody/aptamer-based platforms have allowed the generation of novel cellular, spatial, and post-translational dimensions as well as innovative facets in biomarker validation and druggable target identification.

EXPERT OPINION: Proteomics is a powerful toolbox to functionally characterize, quantify and localize the extensive protein catalog of the human brain across physiological and pathological states. Brain function depends on multi-dimensional protein homeostasis and its elucidation will help us to characterize biological pathways that are essential to properly maintain cognitive functions. In addition, comprehensive human brain pathological proteomes may be the basis in computational drug-repositioning methods as a strategy for unveiling potential new therapies in neurodegenerative and psychiatric disorders.

PMID:38299555 | DOI:10.1080/14789450.2024.2313073

Front Immunol. 2024 Jan 17;14:1281744. doi: 10.3389/fimmu.2023.1281744. eCollection 2023.

ABSTRACT

To improve the efficacy of immune checkpoint inhibitors (ICIs) for cancer treatment, various strategies, including combination therapies with repurposed drugs, are being explored. Several readily available interventions with potential to enhance programmed death 1 (PD-1) blockade have been identified. However, these interventions often remain overlooked due to the lack of financial incentives for their development, making them financial orphans. This review summarizes current knowledge regarding off-label drugs, supplements, and other readily available interventions that could improve the efficacy of PD-1 blockade. The summary of each intervention includes the proposed mechanism of action for combination with checkpoint inhibitors and data from animal and human studies. Additionally, we include summaries of common interventions to be avoided by patients on PD-1 blockade. Finally, we present approaches for conducting further studies in patients, with the aim of expediting the clinical development of these interventions. We strive to increase awareness of readily available combination therapies that may advance cancer immunotherapy and help patients today.

PMID:38299150 | PMC:PMC10827885 | DOI:10.3389/fimmu.2023.1281744

Front Med (Lausanne). 2024 Jan 17;11:1352803. doi: 10.3389/fmed.2024.1352803. eCollection 2024.

ABSTRACT

Repurposing is one of the key opportunities to address the unmet rare diseases therapeutic need. Based on cases of drug repurposing in small population conditions, and previous work in drug repurposing, we analyzed the most important lessons learned, such as the sharing of clinical observations, reaching out to regulatory scientific advice at an early stage, and public-private collaboration. In addition, current upcoming trends in the field of drug repurposing in rare diseases were analyzed, including the role these trends could play in the rare diseases' ecosystem. Specifically, we cover the opportunities of innovation platforms, the use of real-world data, the use of artificial intelligence, regulatory initiatives in repurposing, and patient engagement throughout the repurposing project. The outcomes from these emerging activities will help progress the field of drug repurposing for the benefit of patients, public health and medicines development.

PMID:38298814 | PMC:PMC10828010 | DOI:10.3389/fmed.2024.1352803

Biol Pharm Bull. 2024;47(2):345-349. doi: 10.1248/bpb.b23-00831.

ABSTRACT

The mechanisms of several drugs remain unclear, limiting our understanding of how they exert their effects. Receptor affinities have not been comprehensively measured during drug development, and the safety investigations in humans are limited. Therefore, numerous unknown adverse and beneficial effects of drugs in humans persist. In this review, I highlight our achievements in identifying the unexpected beneficial effects of drugs through the analysis of real-world clinical data, which can contribute to drug repositioning and target finding. (1) Through the analysis of real-world data, we found that the anti-arrhythmic amiodarone induced interstitial lung disease, leading to fibrosis. Surprisingly, concurrent use of an anti-thrombin drug, dabigatran mitigated these adverse events. Pharmacological studies using animal models have mimicked this phenomenon and revealed the molecular mechanisms associated with the platelet-derived growth factor-alpha receptors. (2) The antidiabetic dipeptidyl-peptidase 4 inhibitors increased the risk of an autoimmune disease, bullous pemphigoid, which was reduced by the concomitant use of lisinopril. Pharmacological studies using human peripheral blood mononuclear cells have revealed that lisinopril suppressed the skin disorders by inhibiting the expression of cutaneous matrix metalloproteinase 9 in macrophages. (3) The antimicrobial fluoroquinolones increased the risk of tendinopathy, which was reduced by the concomitant use of dexamethasone. However, clinical guidelines have suggested that corticosteroid increases the risk of tendinopathy. Our investigation demonstrated that fluoroquinolones impaired tendon cells through DNA damage by generating reactive oxygen species. In contrast, dexamethasone exhibited an acute beneficial effect on tendon tissue by upregulating the expression of a radical scavenger, glutathione peroxidase 3.

PMID:38296548 | DOI:10.1248/bpb.b23-00831

Alzheimers Res Ther. 2024 Jan 31;16(1):23. doi: 10.1186/s13195-023-01355-x.

ABSTRACT

BACKGROUND: Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer's Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60-79 years) at increased risk of dementia.

METHODS: MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded.

CONCLUSION: MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field.

TRIAL REGISTRATION: ClinicalTrials.gov (NCT05109169).

PMID:38297399 | DOI:10.1186/s13195-023-01355-x

ACS Infect Dis. 2024 Jan 31. doi: 10.1021/acsinfecdis.3c00371. Online ahead of print.

ABSTRACT

In the recent decade, scientific communities have toiled to tackle the emerging burden of drug-resistant tuberculosis (DR-TB) and rapidly growing opportunistic nontuberculous mycobacteria (NTM). Among these, two neglected mycobacteria species of the Acinetobacter family, Mycobacterium leprae and Mycobacterium ulcerans, are the etiological agents of leprosy and Buruli ulcer infections, respectively, and fall under the broad umbrella of neglected tropical diseases (NTDs). Unfortunately, lackluster drug discovery efforts have been made against these pathogenic bacteria in the recent decade, resulting in the discovery of only a few countable hits and majorly repurposing anti-TB drug candidates such as telacebec (Q203), P218, and TB47 for current therapeutic interventions. Major ignorance in drug candidate identification might aggravate the dramatic consequences of rapidly spreading mycobacterial NTDs in the coming days. Therefore, this Review focuses on an up-to-date account of drug discovery efforts targeting selected druggable targets from both bacilli, including the accompanying challenges that have been identified and are responsible for the slow drug discovery. Furthermore, a succinct discussion of the all-new possibilities that could be alternative solutions to mitigate the neglected mycobacterial NTD burden and subsequently accelerate the drug discovery effort is also included. We anticipate that the state-of-the-art strategies discussed here may attract major attention from the scientific community to navigate and expand the roadmap for the discovery of next-generation therapeutics against these NTDs.

PMID:38295025 | DOI:10.1021/acsinfecdis.3c00371

IEEE J Biomed Health Inform. 2024 Jan 31;PP. doi: 10.1109/JBHI.2024.3360437. Online ahead of print.

ABSTRACT

Predicting potential drug-disease associations (RDAs) plays a pivotal role in elucidating therapeutic strategies for diseases and facilitating drug repositioning, making it of paramount importance. However, existing methods are constrained and rely heavily on limited domain-specific knowledge, impeding their ability to effectively predict candidate associations between drugs and diseases. Moreover, the simplistic definition of unknown information pertaining to drug-disease relationships as negative samples presents inherent limitations. To overcome these challenges, we introduce a novel hierarchical negative sampling-based graph contrastive model, termed HSGCLRDA, which aims to forecast latent associations between drugs and diseases. In this study, HSGCLRDA integrates the association information as well as similarity between drugs, diseases and proteins. Meanwhile, the model constructs a drug-disease-protein heterogeneous network. Subsequently, employing a hierarchical structural sampling technique, we establish reliable negative drug-disease samples utilizing PageRank algorithms. Utilizing meta-path aggregation within the heterogeneous network, we derive low-dimensional representations for drugs and diseases, thereby constructing global and local feature graphs that capture their interactions comprehensively. To obtain representation information, we adopt a self-supervised graph contrastive approach that leverages graph convolutional networks (GCNs) and second-order GCNs to extract feature graph information. Furthermore, we integrate a contrastive cost function derived from the cross-entropy cost function, facilitating holistic model optimization. Experimental results obtained from benchmark datasets not only showcase the superior performance of HSGCLRDA compared to various baseline methods in predicting RDAs but also emphasize its practical utility in identifying novel potential diseases associated with existing drugs through meticulous case studies.

PMID:38294927 | DOI:10.1109/JBHI.2024.3360437

J Mycol Med. 2024 Jan 24;34(1):101462. doi: 10.1016/j.mycmed.2024.101462. Online ahead of print.

ABSTRACT

Keratoplasty represents a risk factor for fungal eye infections, despites the antibacterial actives in the corneal tissue preservation means, it does not contain active substances with antifungal action. Among the most commonly associated fungal agents are the species belonging to the genera Fusarium and Candida. These agents can trigger an infectious process characterized by swift progression associated with high rates of morbidity, causing irreversible damage. Polyene and azole antifungals are the main agents of ocular therapy, however, they demonstrate some limitations, such as their toxicity and fungal resistance. In this context, drug repositioning and the combination of antifungals may be an alternative. Hence, the goal of this study was to investigate the potential activity of clioquinol (CLQ), a derivative of 8-hydroxyquinoline with previously described antifungal activity, along with its triple and quadruple combinations with antifungal agents commonly used in ophthalmic fungal therapy, natamycin (NAT), voriconazole (VRC), and amphotericin B (AMB), against main fungal pathogens in eye infections. The MICs for CLQ ranged from 0.25 to 2.0 μg/mL, for NAT from 4.0 to 32.0 μg/mL, for AMB it ranged from 0.25 to 16.0 μg/mL and for VRC from 0.03125 to 512.0 µg/mL. Among the tested combinations, the VRC-AMB-CLQ combination stands out, which showed a synergistic effect for more than 50 % of the tested strains and did not present antagonistic results against any of them. Toxicity data were similar to those antifungals already used, even with lower potential toxicity. Therefore, both clioquinol and the triple combination VCR-AMB-CLQ exhibited promising profiles for use as active components in corneal tissue preservation medium.

PMID:38290229 | DOI:10.1016/j.mycmed.2024.101462

Arch Med Res. 2024 Jan 29;55(2):102958. doi: 10.1016/j.arcmed.2024.102958. Online ahead of print.

ABSTRACT

BACKGROUND: Chagas disease and cutaneous leishmaniasis, two parasitic diseases caused by Trypanosoma cruzi (T. cruzi) and Leishmania mexicana (L. mexicana), respectively, have a major global impact. Current pharmacological treatments for these diseases are limited and can cause severe side effects; thus, there is a need for new antiprotozoal drugs.

METHODS: Using molecular docking, this work describes a structure-based virtual screening of an FDA-approved drug library against Trypanosoma cruzi and Leishmania mexicana glycolytic enzyme triosephosphate isomerase (TIM), which is highly conserved in these parasites. The selected compounds with potential dual inhibitory activity were tested in vitro to confirm their biological activity.

RESULTS: The study showed that five compounds: nilotinib, chlorhexidine, protriptyline, cyproheptadine, and montelukast, were more active against T. cruzi, than the reference drugs, nifurtimox and benznidazole while chlorhexidine and protriptyline were the most active against L. mexicana.

CONCLUSIONS: The analysis of these compounds and their structural characteristics may provide the basis for the development of new antiprotozoal agents.

PMID:38290200 | DOI:10.1016/j.arcmed.2024.102958

Curr Mol Med. 2024 Jan 4. doi: 10.2174/0115665240270426231123155924. Online ahead of print.

ABSTRACT

Obesity dramatically increases the risk of type 2 diabetes, fatty liver, hypertension, cardiovascular disease, and cancer, causing both declines in quality of life and life expectancy, which is a serious worldwide epidemic. At present, more and more patients with obesity are choosing drug therapy. However, given the high failure rate, high cost, and long design and testing process for discovering and developing new anti-obesity drugs, drug repurposing could be an innovative method and opportunity to broaden and improve pharmacological tools in this context. Because different diseases share molecular pathways and targets in the cells, anti-obesity drugs discovered in other fields are a viable option for treating obesity. Recently, some drugs initially developed for other diseases, such as treating diabetes, tumors, depression, alcoholism, erectile dysfunction, and Parkinson's disease, have been found to exert potential anti-obesity effects, which provides another treatment prospect. In this review, we will discuss the potential benefits and barriers associated with these drugs being used as obesity medications by focusing on their mechanisms of action when treating obesity. This could be a viable strategy for treating obesity as a significant advance in human health.

PMID:38289639 | DOI:10.2174/0115665240270426231123155924

Infect Disord Drug Targets. 2024 Jan 29. doi: 10.2174/0118715265270637240107153121. Online ahead of print.

ABSTRACT

BACKGROUND: Severe COVID-19 or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a kind of viral pneumonia induced by infection with the coronavirus that causes ARDS. It involves symptoms that are a combination of viral pneumonia and ARDS. Antiviral or immunosuppressive medicines are used to treat many COVID-19 patients. Several drugs are now undergoing clinical studies in order to see if they can be repurposed in the future.

MATERIAL AND METHODS: In this study, in silico biomarker-targeted methodologies, such as target/molecule virtual screening by docking technique and drug repositioning strategy, as well as data mining approach and meta-analysis of investigational data, were used.

RESULTS: In silico findings of used combination of drug repurposing and high-throughput docking methods presented acetaminophen, ursodiol, and β-carotene as a three-drug therapy regimen to treat ARDS induced by viral pneumonia in addition to inducing direct antiviral effects against COVID-19 viral infection.

CONCLUSION: In the current study, drug repurposing and high throughput docking methods have been employed to develop combination drug regimens as multiple-molecule drugs for the therapy of COVID-19 and ARDS based on a multiple-target therapy strategy. This approach offers a promising avenue for the treatment of COVID-19 and ARDS, and highlights the potential benefits of drug repurposing in the fight against the current pandemic.

PMID:38288808 | DOI:10.2174/0118715265270637240107153121

J Biomol Struct Dyn. 2024 Jan 29:1-29. doi: 10.1080/07391102.2024.2308769. Online ahead of print.

ABSTRACT

The emergence of new SARS-CoV-2 variants has raised concerns about the effectiveness of COVID-19 vaccines. To address this challenge, small-molecule antivirals have been proposed as a crucial therapeutic option. Among potential targets for anti-COVID-19 therapy, the main protease (Mpro) of SARS-CoV-2 is important due to its essential role in the virus's life cycle and high conservation. The substrate-binding region of the core proteases of various coronaviruses, including SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV), could be used for the generation of new protease inhibitors. Various drug discovery methods have employed a diverse range of strategies, targeting both monomeric and dimeric forms, including drug repurposing, integrating virtual screening with high-throughput screening (HTS), and structure-based drug design, each demonstrating varying levels of efficiency. Covalent inhibitors, such as Nirmatrelvir and MG-101, showcase robust and high-affinity binding to Mpro, exhibiting stable interactions confirmed by molecular docking studies. Development of effective antiviral drugs is imperative to address potential pandemic situations. This review explores recent advances in the search for Mpro inhibitors and the application of artificial intelligence (AI) in drug design. AI leverages vast datasets and advanced algorithms to streamline the design and identification of promising Mpro inhibitors. AI-driven drug discovery methods, including molecular docking, predictive modeling, and structure-based drug repurposing, are at the forefront of identifying potential candidates for effective antiviral therapy. In a time when COVID-19 potentially threat global health, the quest for potent antiviral solutions targeting Mpro could be critical for inhibiting the virus.Communicated by Ramaswamy H. Sarma.

PMID:38287509 | DOI:10.1080/07391102.2024.2308769

J Biomol Struct Dyn. 2024 Jan 29:1-13. doi: 10.1080/07391102.2024.2308764. Online ahead of print.

ABSTRACT

cAMP-specific 3',5'-cyclic phosphodiesterase 4 A (PDE4A) holds a pivotal role in modulating intracellular levels of cyclic adenosine monophosphate (cAMP). Targeting PDE4A with novel therapeutic agents shows promise in addressing neurological disorders (e.g. Alzheimer's and Parkinson's diseases), mood disorders (depression, anxiety), inflammatory conditions (asthma, chronic obstructive pulmonary disease), and even cancer. In this study, we present a comprehensive approach that integrates virtual screening and molecular dynamics (MD) simulations to identify potential inhibitors of PDE4A from the existing pool of FDA-approved drugs. The initial compound selection was conducted focusing on binding affinity scores, which led to the identification of several high-affinity compounds with potential PDE4A binding properties. From the refined selection process, two promising compounds, Fluspirilene and Dihydroergocristine, emerged as strong candidates, displaying substantial affinity and specificity for the PDE4A binding site. Interaction analysis provided robust evidence of their binding capabilities. To gain deeper insights into the dynamic behavior of Fluspirilene and Dihydroergocristine in complex with PDE4A, we conducted 300 ns MD simulations, principal components analysis (PCA), and free energy landscape (FEL) analysis. These analyses revealed that Fluspirilene and Dihydroergocristine binding stabilized the PDE4A structure and induced minimal conformational changes, highlighting their potential as potent binders. In conclusion, our study systematically explores repurposing existing FDA-approved drugs as PDE4A inhibitors through a comprehensive virtual screening pipeline. The identified compounds, Fluspirilene and Dihydroergocristine, exhibit a strong affinity for PDE4A, displaying characteristics that support their suitability for further development as potential therapeutic agents for conditions associated with PDE4A dysfunction.Communicated by Ramaswamy H. Sarma.

PMID:38287492 | DOI:10.1080/07391102.2024.2308764

ACS Omega. 2024 Jan 10;9(3):3793-3806. doi: 10.1021/acsomega.3c07296. eCollection 2024 Jan 23.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disorder characterized by the loss of upper and lower motor neurons, resulting in debilitating muscle weakness and atrophy. Currently, there are no effective treatments available for ALS, posing significant challenges in managing the disease that affects approximately two individuals per 100,000 people annually. To address the urgent need for effective ALS treatments, we conducted a drug repurposing study using a combination of bioinformatics tools and molecular docking techniques. We analyzed sporadic ALS-related genes from the GEO database and identified key signaling pathways involved in sporadic ALS pathogenesis through pathway analysis using DAVID. Subsequently, we utilized the Clue Connectivity Map to identify potential drug candidates and performed molecular docking using AutoDock Vina to evaluate the binding affinity of short-listed drugs to key sporadic ALS-related genes. Our study identified Cefaclor, Diphenidol, Flubendazole, Fluticasone, Lestaurtinib, Nadolol, Phenamil, Temozolomide, and Tolterodine as potential drug candidates for repurposing in sporadic ALS treatment. Notably, Lestaurtinib demonstrated high binding affinity toward multiple proteins, suggesting its potential as a broad-spectrum therapeutic agent for sporadic ALS. Additionally, docking analysis revealed NOS3 as the gene that interacts with all the short-listed drugs, suggesting its possible involvement in the mechanisms underlying the therapeutic potential of these drugs in sporadic ALS. Overall, our study provides a systematic framework for identifying potential drug candidates for sporadic ALS therapy and highlights the potential of drug repurposing as a promising strategy for discovering new therapies for neurodegenerative diseases.

PMID:38284068 | PMC:PMC10809234 | DOI:10.1021/acsomega.3c07296

J Orthop Translat. 2024 Jan 6;44:88-101. doi: 10.1016/j.jot.2023.09.003. eCollection 2024 Jan.

ABSTRACT

BACKGROUND: Mutations in Slc26a2 cause a spectrum of autosomal-recessive chondrodysplasia with a significant and negligible influence on the quality of life. It has been reported that Slc26a2 deficiency triggers the ATF6 branch of the UPR, which may, in turn, activate the negative regulator of the FGFR3 signaling pathway. However, the correlation between the deletion of Slc26a2 and the augmentation of downstream phosphorylation of FGFR3 has not been investigated in vivo.

METHODS: First, we constructed Slc26a2 and Fgfr3 double knockout mouse lines and observed gross views of the born mice and histological staining of the tibial growth plates. The second approach was to construct tamoxifen-inducible Cre-ERT2 mouse models to replicate SLC26A2-related non-lethal dysplastic conditions. Pharmacological intervention was performed by administering the FGFR3 inhibitor NVP-BGJ398. The effect of NVP-BGJ398 on chondrocytes was assessed by Alcian blue staining, proliferation, apoptosis, and chondrocyte-specific markers and then verified by western blotting for variations in the downstream markers of FGFR3. The growth process was detected using X-rays, micro-CT examination, histomorphometry staining of growth plates, and immunofluorescence.

RESULTS: Genetic ablation of Fgfr3 in embryonic Slc26a2-deficient chondrocytes slightly attenuated chondrodysplasia. Subsequently, in the constructed mild dysplasia model, we found that postnatal intervention with Fgfr3 gene in Slc26a2-deficient chondrocytes partially alleviated chondrodysplasia. In chondrocyte assays, NVP-BGJ398 suppressed the defective phenotype of Slc26a2-deficient chondrocytes and restored the phosphorylation downstream of FGFR3 in a concentration-dependent manner. In addition, in vivo experiments showed significant alleviation of impaired chondrocyte differentiation, and micro-CT analysis showed a clear improvement in trabecular bone microarchitectural parameters.

CONCLUSION: Our results suggested that inhibition of FGFR3 signaling pathway overactivation and NVP-BGJ398 has promising therapeutic implications for the development of SLC26A2-related skeletal diseases in humans.

THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our data provide genetic and pharmacological evidence that targeting FGFR3 signaling via NVP-BGJ398 could be a route for the treatment of SLC26A2-associated skeletal disorders, which promisingly advances translational applications and therapeutic development.

PMID:38282752 | PMC:PMC10818158 | DOI:10.1016/j.jot.2023.09.003

Bioinform Adv. 2023 Aug 26;3(1):vbad116. doi: 10.1093/bioadv/vbad116. eCollection 2023.

ABSTRACT

MOTIVATION: Accurate identification of target proteins that interact with drugs is a vital step in silico, which can significantly foster the development of drug repurposing and drug discovery. In recent years, numerous deep learning-based methods have been introduced to treat drug-target interaction (DTI) prediction as a classification task. The output of this task is binary identification suggesting the absence or presence of interactions. However, existing studies often (i) neglect the unique molecular attributes when embedding drugs and proteins, and (ii) determine the interaction of drug-target pairs without considering biological interaction information.

RESULTS: In this study, we propose an end-to-end attention-derived method based on the self-attention mechanism and graph neural network, termed SAGDTI. The aim of this method is to overcome the aforementioned drawbacks in the identification of DTI. SAGDTI is the first method to sufficiently consider the unique molecular attribute representations for both drugs and targets in the input form of the SMILES sequences and three-dimensional structure graphs. In addition, our method aggregates the feature attributes of biological information between drugs and targets through multi-scale topologies and diverse connections. Experimental results illustrate that SAGDTI outperforms existing prediction models, which benefit from the unique molecular attributes embedded by atom-level attention and biological interaction information representation aggregated by node-level attention. Moreover, a case study on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shows that our model is a powerful tool for identifying DTIs in real life.

AVAILABILITY AND IMPLEMENTATION: The data and codes underlying this article are available in Github at https://github.com/lixiaokun2020/SAGDTI.

PMID:38282612 | PMC:PMC10818136 | DOI:10.1093/bioadv/vbad116