BMC Cancer. 2023 Feb 23;23(1):185. doi: 10.1186/s12885-023-10659-y.

ABSTRACT

BACKGROUND: Glioblastoma, the most common primary malignant brain tumour in adults, is a highly vascular tumour characterised by abnormal angiogenesis. Additional mechanisms of tumour vascularisation have also been reported in glioblastoma, including the formation of tumour cell-derived vessels by vasculogenic mimicry (VM) or the transdifferentiation of tumour cells to endothelial cells. VM and endothelial transdifferentiation have frequently been reported as distinct processes, however, the use of both terms to describe a single process of vascularisation also occurs. Some overlapping characteristics have also been reported when identifying each process. We therefore aimed to determine the markers consistently attributed to VM and endothelial transdifferentiation in the glioblastoma literature.

METHODS: Ovid MEDLINE and Ovid Embase were searched for studies published between January 1999 and July 2021 that assessed VM or tumour to endothelial transdifferentiation in human glioblastoma. The online systematic review tool Covidence was used for screening and data extraction. Extracted data included type of tumour-derived vasculature reported, methods and techniques used, and markers investigated. Studies were grouped based on type of vasculature reported for further assessment.

RESULTS: One hundred and thirteen of the 419 unique records identified were included for analysis. VM was reported in 64/113 studies, while tumour to endothelial transdifferentiation was reported in 16/113 studies. The remaining studies used both terms to describe a single process, did not define the process that occurred, or concluded that neither VM nor endothelial transdifferentiation occurred. Absence of CD34 and/or CD31 in vascular structures was the most common indicator of VM, while expression of CD34 and/or CD31, in addition to various other endothelial, stem cell or tumour cell markers, indicated tumour to endothelial transdifferentiation.

CONCLUSION: Cells derived from tumour to endothelial transdifferentiation express typical endothelial markers including CD34 and CD31, while tumour cells contributing to VM lack CD34 and CD31 expression. Additional tumour markers are required to identify transdifferentiation in glioblastoma tissue, and this process requires further characterisation.

PMID:36823554 | DOI:10.1186/s12885-023-10659-y

Medicine (Baltimore). 2023 Feb 10;102(6):e31318. doi: 10.1097/MD.0000000000031318.

ABSTRACT

In December 2019, a COVID-19 outbreak caused by SARS-CoV-2 raised worldwide health concerns. In this case, molecular docking and drug repurposing computational approaches were engaged to check the efficiency of plant-based inhibitory compounds against SARS-CoV-2 main protease enzyme and papain-like protease enzyme. Twenty phytochemical inhibitory compounds were collected. Then these compounds were screened based on Lipinski's rule. As a result of this screening eleven compounds were further selected. Quantitative structure-activity relationships analysis was done before molecular docking to check especially the antiviral activity of inhibitory compounds. Docking validation of these compounds was checked by using online server Database of Useful Decoys: Enhanced. Binding affinity value, and pharmacokinetic properties of Aloin compound indicated that it can be used against main protease enzyme of SARS-CoV-2. So, it makes it a promising compound to follow further in cell and biochemical-based assays to explore its potential use against COVID-19.

PMID:36820539 | DOI:10.1097/MD.0000000000031318

Front Mol Biosci. 2023 Feb 1;10:1145834. doi: 10.3389/fmolb.2023.1145834. eCollection 2023.

NO ABSTRACT

PMID:36818044 | PMC:PMC9929556 | DOI:10.3389/fmolb.2023.1145834

Stat Med. 2023 Feb 23. doi: 10.1002/sim.9686. Online ahead of print.

ABSTRACT

Linkage between drug claims data and clinical outcome allows a data-driven experimental approach to drug repurposing. We develop an estimation procedure based on generalized random forests for estimation of time-point specific average treatment effects in a time-to-event setting with competing risks. To handle right-censoring, we propose a two-step procedure for estimation, applying inverse probability weighting to construct time-point specific weighted outcomes as input for the generalized random forest. The generalized random forests adaptively handle covariate effects on the treatment assignment by applying a splitting rule that targets a causal parameter. Using simulated data we demonstrate that the method is effective for a causal search through a list of treatments to be ranked according to the magnitude of their effect on clinical outcome. We illustrate the method using the Danish national health registries where it is of interest to discover drugs with an unexpected protective effect against relapse of severe depression.

PMID:36815690 | DOI:10.1002/sim.9686

Acta Pharm Sin B. 2023 Jan;13(1):54-67. doi: 10.1016/j.apsb.2022.05.004. Epub 2022 May 12.

ABSTRACT

Prediction of the interactions between small molecules and their targets play important roles in various applications of drug development, such as lead discovery, drug repurposing and elucidation of potential drug side effects. Therefore, a variety of machine learning-based models have been developed to predict these interactions. In this study, a model called auxiliary multi-task graph isomorphism network with uncertainty weighting (AMGU) was developed to predict the inhibitory activities of small molecules against 204 different kinases based on the multi-task Graph Isomorphism Network (MT-GIN) with the auxiliary learning and uncertainty weighting strategy. The calculation results illustrate that the AMGU model outperformed the descriptor-based models and state-of-the-art graph neural networks (GNN) models on the internal test set. Furthermore, it also exhibited much better performance on two external test sets, suggesting that the AMGU model has enhanced generalizability due to its great transfer learning capacity. Then, a naïve model-agnostic interpretable method for GNN called edges masking was devised to explain the underlying predictive mechanisms, and the consistency of the interpretability results for 5 typical epidermal growth factor receptor (EGFR) inhibitors with their structure‒activity relationships could be observed. Finally, a free online web server called KIP was developed to predict the kinome-wide polypharmacology effects of small molecules (http://cadd.zju.edu.cn/kip).

PMID:36815050 | PMC:PMC9939366 | DOI:10.1016/j.apsb.2022.05.004

Acta Pharm Sin B. 2023 Jan;13(1):142-156. doi: 10.1016/j.apsb.2022.04.003. Epub 2022 Apr 9.

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and macrophage polarization plays an important role in its pathogenesis. However, which molecule regulates macrophage polarization in NAFLD remains unclear. Herein, we showed NAFLD mice exhibited increased 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7) expression in hepatic macrophages concomitantly with elevated M1 polarization. Single-cell RNA sequencing on hepatic non-parenchymal cells isolated from wild-type littermates and macrophage-17β-HSD7 knockout mice fed with high fat diet (HFD) for 6 weeks revealed that lipid metabolism pathways were notably changed. Furthermore, 17β-HSD7 deficiency in macrophages attenuated HFD-induced hepatic steatosis, insulin resistance and liver injury. Mechanistically, 17β-HSD7 triggered NLRP3 inflammasome activation by increasing free cholesterol content, thereby promoting M1 polarization of macrophages and the secretion of pro-inflammatory cytokines. In addition, to help demonstrate that 17β-HSD7 is a potential drug target for NAFLD, fenretinide was screened out from an FDA-approved drug library based on its 17β-HSD7 dehydrogenase inhibitory activity. Fenretinide dose-dependently abrogated macrophage polarization and pro-inflammatory cytokines production, and subsequently inhibited fat deposition in hepatocytes co-cultured with macrophages. In conclusion, our findings suggest that blockade of 17β-HSD7 signaling by fenretinide would be a drug repurposing strategy for NAFLD treatment.

PMID:36815031 | PMC:PMC9939369 | DOI:10.1016/j.apsb.2022.04.003

Front Cardiovasc Med. 2023 Feb 6;10:1033832. doi: 10.3389/fcvm.2023.1033832. eCollection 2023.

ABSTRACT

Cardiovascular/renal/metabolic (CVRM) diseases collectively comprise the leading cause of death worldwide and disproportionally affect older demographics and historically underrepresented minority populations. Despite these critical unmet needs, pharmaceutical research and development (R&D) efforts have historically struggled with high drug failure rates, low approval rates, and other challenges. Drug repurposing is one approach to recovering R&D costs and meeting unmet demands in therapeutic markets. While there are multiple approaches to conducting drug repurposing, we recognize the importance of bringing together and consolidating discontinued drug information to help identify prospective repurposing candidates. In this study, we have harmonized and integrated information on all relevant CVRM drug assets from U.S. Securities and Exchange Commission (SEC) filings, clinical trial records, PharmGKB, Open Targets, and other platforms. A list of existing therapeutics discontinued or shelved by pharmaceutical/biotechnology companies in 2011-2022 were manually curated and interpreted for insights using information on each drug's genetic target, mechanism of action (MOA), clinical indication, and R&D information including highest phase of clinical development, year of discontinuation, previous repurposing attempts (if any), and other actionable metadata. This study also summarizes the profiles of CVRM drugs discontinued within the past decade and identifies the limitations of publicly available information on discontinued drug assets. The constructed database could serve as a tool for identifying candidates for drug repurposing and developing query methods for collecting R&D information.

PMID:36815023 | PMC:PMC9940660 | DOI:10.3389/fcvm.2023.1033832

Bioinform Biol Insights. 2023 Feb 17;17:11779322231155068. doi: 10.1177/11779322231155068. eCollection 2023.

ABSTRACT

Hepatic encephalopathy (HE) is a set of complex neurological complications that arise from advanced liver disease. The precise molecular and cellular mechanism of HE is not fully understood. Differentially expressed genes (DEGs) from microarray technologies are powerful approaches to obtain new insight into the pathophysiology of HE. We analyzed microarray data sets of cirrhotic patients with HE from Gene Expression Omnibus to identify DEGs in postmortem cerebral tissues. Consequently, we uploaded significant DEGs into the STRING to specify protein-protein interactions. Cytoscape was used to reconstruct the genetic network and identify hub genes. Target genes were uploaded to different databases to perform comprehensive enrichment analysis and repurpose new therapeutic options for HE. A total of 457 DEGs were identified in 2 data sets totally from 12 cirrhotic patients with HE compared with 12 healthy subjects. We found that 274 genes were upregulated and 183 genes were downregulated. Network analyses on significant DEGs indicated 12 hub genes associated with HE. Enrichment analysis identified fatty acid beta-oxidation, cerebral organic acidurias, and regulation of actin cytoskeleton as main involved pathways associated with upregulated genes; serotonin receptor 2 and ELK-SRF/GATA4 signaling, GPCRs, class A rhodopsin-like, and p38 MAPK signaling pathway were related to downregulated genes. Finally, we predicted 39 probable effective drugs/agents for HE. This study not only confirms main important involved mechanisms of HE but also reveals some yet unknown activated molecular and cellular pathways in human HE. In addition, new targets were identified that could be of value in the future study of HE.

PMID:36814683 | PMC:PMC9940182 | DOI:10.1177/11779322231155068

Nat Commun. 2023 Feb 22;14(1):993. doi: 10.1038/s41467-023-36637-3.

ABSTRACT

Single-cell RNA sequencing technology has enabled in-depth analysis of intercellular heterogeneity in various diseases. However, its full potential for precision medicine has yet to be reached. Towards this, we propose A Single-cell Guided Pipeline to Aid Repurposing of Drugs (ASGARD) that defines a drug score to recommend drugs by considering all cell clusters to address the intercellular heterogeneity within each patient. ASGARD shows significantly better average accuracy on single-drug therapy compared to two bulk-cell-based drug repurposing methods. We also demonstrated that it performs considerably better than other cell cluster-level predicting methods. In addition, we validate ASGARD using the drug response prediction method TRANSACT with Triple-Negative-Breast-Cancer patient samples. We find that many top-ranked drugs are either approved by the Food and Drug Administration or in clinical trials treating corresponding diseases. In conclusion, ASGARD is a promising drug repurposing recommendation tool guided by single-cell RNA-seq for personalized medicine. ASGARD is free for educational use at https://github.com/lanagarmire/ASGARD .

PMID:36813801 | DOI:10.1038/s41467-023-36637-3

J Infect Public Health. 2023 Feb 10;16(4):554-572. doi: 10.1016/j.jiph.2023.02.005. Online ahead of print.

ABSTRACT

BACKGROUND: The emergence of various drug-resistant strains of Mycobacterium tuberculosis compelled medicinal chemists to expedite the discovery of novel, safer alternatives to present regimens. Decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1), an essential component of arabinogalactan biosynthesis, has been considered a novel target for developing new inhibitors against Tuberculosis. We aimed to discover DprE1 inhibitors utilizing the drug repurposing approach.

METHODS: A structure-based virtual screening of FDA and world-approved drugs database was carried out, and initially, 30 molecules were selected based on their binding affinity. These compounds were further analyzed by molecular docking with extra-precision mode, MMGBSA binding free energy estimation, and prediction of ADMET profile.

RESULTS: Based on the docking results and MMGBSA energy values- ZINC000006716957, ZINC000011677911, and ZINC000022448696 were identified to be the top three hit molecules with good binding interactions inside the active site of DprE1. These hit molecules were subjected to molecular dynamics (MD) simulation for a period of 100 ns to study the dynamic nature of the binding complex. MD results were in accordance with molecular docking and MMGBSA analysis showing protein-ligand contacts with key amino acid residues of DprE1.

CONCLUSION: Based on their stability throughout the 100 ns simulation, ZINC000011677911 was the best in silico hit with an already known safety profile. This molecule could lead to future optimization and development of new DprE1 inhibitors.

PMID:36812878 | DOI:10.1016/j.jiph.2023.02.005

J Mycol Med. 2023 Feb 11;33(2):101361. doi: 10.1016/j.mycmed.2023.101361. Online ahead of print.

ABSTRACT

INTRODUCTION: The treatment of Cryptococcus neoformans with fluconazole and amphotericin B is, at times, characterised by clinical failure. Therefore, this study sought to re-purpose primaquine (PQ) as an anti-Cryptococcus compound.

METHOD: The susceptibility profile of some cryptococcal strains towards PQ was determined using EUCAST guidelines, and PQ's mode of action was examined. In the end, the ability of PQ to enhance in vitro macrophage phagocytosis was also assessed.

RESULTS: We show that PQ had a significant inhibitory effect on the metabolic activity of all tested cryptococcal strains, with 60 µM, defined as MIC50 in this preliminary study, as it reduced the metabolic activity by more than 50%. Moreover, at this concentration, the drug was able to affect mitochondrial function adversely, as treated cells displayed significant (p < 0.05) loss of mitochondrial membrane potential, cytochrome c (cyt c) leakage and overproduction of reactive oxygen species (ROS) when compared to non-treated cells. It is our reasoned summation that the produced ROS targeted the cell walls and cell membranes, inducing observable ultrastructural changes and a significant (p < 0.05) increase in membrane permeability when compared to non-treated cells. Concerning the PQ effect on macrophages, it was noted that it significantly (p < 0.05) enhanced macrophage phagocytic efficiency compared to non-treated macrophages.

CONCLUSION: This preliminary study highlights the potential of PQ to inhibit the in vitro growth of cryptococcal cells. Moreover, PQ could control the proliferation of cryptococcal cells inside macrophages, which they often manipulate in a Trojan horse-like manner.

PMID:36812704 | DOI:10.1016/j.mycmed.2023.101361

Pharmacol Rep. 2023 Feb 21. doi: 10.1007/s43440-023-00461-9. Online ahead of print.

ABSTRACT

BACKGROUND: Peripheral nerve injuries negatively impact the quality of life of patients, with no effective treatment available that accelerates sensorimotor recovery and promotes functional improvement and pain relief. The aim of this study was to evaluate the effects of diacerein (DIA) in an experimental mice model of sciatic nerve crush.

METHOD: In this study, male Swiss mice were used, randomly separated into six groups as follows: FO (false-operated + vehicle); FO + DIA (false-operated + diacerein 30 mg/kg); SNI (sciatic nerve injury + vehicle); SNI + DIA in doses of 3, 10 and 30 mg/kg (sciatic nerve injury + treatment with diacerein in doses of 3-30 mg/kg). DIA or vehicle was administered 24 h after the surgical procedure, intragastrically, twice a day. The lesion of the right sciatic nerve was generated by crush.

RESULTS: We found that the treatment of animals with DIA accelerated sensorimotor recovery of the animal. In addition, animals in the sciatic nerve injury + vehicle (SNI) group showed hopelessness, anhedonia, and lack of well-being, which were significantly inhibited by DIA treatment. The SNI group showed a reduction in the diameters of nerve fibers, axons, and myelin sheaths, while DIA treatment recovered all these parameters. In addition, the treatment of animals with DIA prevented an increase the levels of interleukin (IL)-1β and a reduction in the levels of the brain-derived growth factor (BDNF).

CONCLUSIONS: Treatment with DIA reduces hypersensitivity and depression like behaviors in animals. Furthermore, DIA promotes functional recovery and regulates IL-1β and BDNF concentrations.

PMID:36809646 | DOI:10.1007/s43440-023-00461-9

Rev Environ Health. 2023 Feb 22. doi: 10.1515/reveh-2023-0001. Online ahead of print.

ABSTRACT

The growing concern about the monkeypox (Mpox) virus infection has garnered a lot of public attention. However, the treatment options available to combat the same is limited to tecovirimat. Additionally, in a possible incidence of resistance, hypersensitivity, or adverse drug reaction, it is imperative to devise and reinforce the second-line therapy. Thus, in this editorial, the authors suggest seven antiviral drugs that could potentially be repurposed to combat the viral illness.

PMID:36809250 | DOI:10.1515/reveh-2023-0001

Assay Drug Dev Technol. 2023 Feb 21. doi: 10.1089/adt.2023.008. Online ahead of print.

NO ABSTRACT

PMID:36809110 | DOI:10.1089/adt.2023.008

J Mol Model. 2023 Feb 20;29(3):70. doi: 10.1007/s00894-023-05457-z.

ABSTRACT

BACKGROUND: In November 2021, variant B.1.1.529 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified by the World Health Organization (WHO) and designated Omicron. Omicron is characterized by a high number of mutations, thirty-two in total, making it more transmissible than the original virus. More than half of those mutations were found in the receptor-binding domain (RBD) that directly interacts with human angiotensin-converting enzyme 2 (ACE2). This study aimed to discover potent drugs against Omicron, which were previously repurposed for coronavirus disease 2019 (COVID-19). All repurposed anti-COVID-19 drugs were compiled from previous studies and tested against the RBD of SARS-CoV-2 Omicron.

METHODS: As a preliminary step, a molecular docking study was performed to investigate the potency of seventy-one compounds from four classes of inhibitors. The molecular characteristics of the best-performing five compounds were predicted by estimating the drug-likeness and drug score. Molecular dynamics simulations (MD) over 100 ns were performed to inspect the relative stability of the best compound within the Omicron receptor-binding site.

RESULTS: The current findings point out the crucial roles of Q493R, G496S, Q498R, N501Y, and Y505H in the RBD region of SARS-CoV-2 Omicron. Raltegravir, hesperidin, pyronaridine, and difloxacin achieved the highest drug scores compared with the other compounds in the four classes, with values of 81%, 57%, 18%, and 71%, respectively. The calculated results showed that raltegravir and hesperidin had high binding affinities and stabilities to Omicron with ΔGbinding of - 75.7304 ± 0.98324 and - 42.693536 ± 0.979056 kJ/mol, respectively. Further clinical studies should be performed for the two best compounds from this study.

PMID:36808314 | DOI:10.1007/s00894-023-05457-z

Cell Rep. 2023 Feb 17;42(2):112137. doi: 10.1016/j.celrep.2023.112137. Online ahead of print.

ABSTRACT

Commonly used antihistamines and other cationic amphiphilic drugs (CADs) are emerging as putative cancer drugs. Their unique chemical structure enables CADs to accumulate rapidly inside lysosomes, where they increase lysosomal pH, alter lysosomal lipid metabolism, and eventually cause lysosomal membrane permeabilization. Here, we show that CAD-induced rapid elevation in lysosomal pH is caused by a lysosomal H+ efflux that requires P2RX4-mediated lysosomal Ca2+ release and precedes the lysosomal membrane permeabilization. The subsequent cytosolic acidification triggers the dephosphorylation, lysosomal translocation, and inactivation of the oncogenic signal transducer and activator of transcription 3 (STAT3) transcription factor. Moreover, CAD-induced lysosomal H+ efflux sensitizes cancer cells to apoptosis induced by STAT3 inhibition and acts synergistically with STAT3 inhibition in restricting the tumor growth of A549 non-small cell lung carcinoma xenografts. These findings identify lysosomal H+ efflux and STAT3 inhibition as anticancer mechanisms of CADs and reinforce the repurposing of safe and inexpensive CADs as cancer drugs with a drug combination strategy.

PMID:36807142 | DOI:10.1016/j.celrep.2023.112137

Comput Biol Med. 2023 Feb 12;155:106671. doi: 10.1016/j.compbiomed.2023.106671. Online ahead of print.

ABSTRACT

De novo drug development is an extremely complex, time-consuming and costly task. Urgent needs for therapies of various diseases have greatly accelerated searches for more effective drug development methods. Luckily, drug repurposing provides a new and effective perspective on disease treatment. Rapidly increased large-scale transcriptome data paints a detailed prospect of gene expression during disease onset and thus has received wide attention in the field of computational drug repurposing. However, how to efficiently mine transcriptome data and identify new indications for old drugs remains a critical challenge. This review discussed the irreplaceable role of transcriptome data in computational drug repurposing and summarized some representative databases, tools and strategies. More importantly, it proposed a practical guideline through establishing the correspondence between three gene expression data types and five strategies, which would facilitate researchers to adopt appropriate strategies to deeply mine large-scale transcriptome data and discover more effective therapies.

PMID:36805225 | DOI:10.1016/j.compbiomed.2023.106671

J Invest Dermatol. 2023 Feb 16:S0022-202X(23)00090-8. doi: 10.1016/j.jid.2023.01.024. Online ahead of print.

ABSTRACT

The prevalence of fibrotic diseases and the lack of pharmacologic modalities to effectively treat them impart particular importance to the discovery of novel anti-fibrotic therapies. The repurposing of drugs with existing mechanisms of action and/or clinical data is a promising approach for treatment of fibrotic diseases. One paradigm that pervades all fibrotic disease is the pathological myofibroblast, a collagen-secreting, contractile mesenchymal cell that is responsible for deposition of fibrotic tissue. Here we use a gene expression paradigm characteristic of activated myofibroblasts in combination with the Connectivity Map in order to select compounds that are predicted to reverse the pathological gene expression signature associated with the myofibroblast and, thus, contain potential for use as anti-fibrotic compounds. We tested a small list of these compounds in a first-pass screen, applying them to human fibroblasts, and identified the retinoic acid receptor agonist Ch55 as potential hit. Further investigation exhibited and elucidated anti-fibrotic effects of Ch55 in vitro, as well as demonstrated anti-scarring activity upon intradermal application in a pre-clinical rabbit ear hypertrophic scar model. We hope that similar predictions to uncover anti-scarring compounds may yield further pre-clinical and, ultimately, clinical success.

PMID:36804965 | DOI:10.1016/j.jid.2023.01.024

Bioorg Med Chem. 2023 Feb 11;81:117212. doi: 10.1016/j.bmc.2023.117212. Online ahead of print.

ABSTRACT

Among the various bacterial infections, tuberculosis continues to hold center stage. Its causative agent, Mycobacterium tuberculosis, possesses robust defense mechanisms against most front-line antibiotic drugs and host responses due to their complex cell membranes with unique lipid molecules. It is now well-established that bacteria change their membrane composition to optimize their environment to survive and elude drug action. Thus targeting membrane or membrane components is a promising avenue for exploiting the chemical space focussed on developing novel membrane-centric anti-bacterial small molecules. These approaches are more effective, non-toxic, and can attenuate resistance phenotype. We present the relevance of targeting the mycobacterial membrane as a practical therapeutic approach. The review highlights the direct and indirect targeting of membrane structure and function. Direct membrane targeting agents cause perturbation in the membrane potential and can cause leakage of the cytoplasmic contents. In contrast, indirect membrane targeting agents disrupt the function of membrane-associated proteins involved in cell wall biosynthesis or energy production. We discuss the chronological chemical improvements in various scaffolds targeting specific membrane-associated protein targets, their clinical evaluation, and up-to-date account of their ''mechanisms of action, potency, selectivity'' and limitations. The sources of anti-TB drugs/inhibitors discussed in this work have emerged from target-based identification, cell-based phenotypic screening, drug repurposing, and natural products. We believe this review will inspire the exploration of uncharted chemical space for informing the development of new scaffolds that can inhibit novel mycobacterial membrane targets.

PMID:36804747 | DOI:10.1016/j.bmc.2023.117212

Recent Adv Antiinfect Drug Discov. 2023 Feb 20. doi: 10.2174/2772434418666230220123217. Online ahead of print.

ABSTRACT

BACKGROUND: Since leprosy bacilli cannot grow in vitro, testing for antimicrobial resistance against Mycobacterium leprae or assessing the anti-leprosy activity of new drugs remains hard. Furthermore, developing a new leprosy drug through the traditional drug development process is not economically captivating for pharmaceutical companies. As a result, repurposing existing drugs/approved medications or their derivatives to test their anti-leprotic potency is a promising alternative. It is an accelerated method to uncover different medicinal and therapeutic properties in approved drug molecules.

AIM: The study aims to explore the binding potential of anti-viral drugs such as Tenofovir, Emtricitabine, and Lamivudine (TEL) against Mycobacterium leprae using molecular docking.

METHODS: The current study evaluated and confirmed the possibility of repurposing anti-viral drugs such as TEL (Tenofovir, Emtricitabine, and Lamivudine) by transferring the graphical window of the BIOVIA DS2017 with the Crystal Structure of a phosphoglycerate mutase gpm1 from Mycobacterium leprae (PDB ID:4EO9). Utilizing the smart minimizer algorithm, the protein's energy was reduced in order to achieve a stable local minima conformation.

RESULTS: The protein and molecule energy minimization protocol generated stable configuration energy molecules. The protein 4EO9 energy was reduced from 14264.5 kcal/mol to -17588.1 kcal/mol.

CONCLUSION: The CHARMm algorithm-based CDOCKER run docked all three molecules (TEL) inside the 4EO9 protein binding pocket (Mycobacterium leprae). The interaction analysis revealed that tenofovir had a better binding molecule with a score of -37.7297 kcal/mol than the other molecules.

PMID:36803758 | DOI:10.2174/2772434418666230220123217