Identification of New Inhibitors for Klebsiella Pneumoniae Trimethoprim-Resistant Dihydrofolate Reductase: An in Silico Drug Repurposing Study

2021 ◽  
Author(s):  
Mostafa Khedrinia ◽  
Farzad Khademi ◽  
Seyed Ali Mirhosseini ◽  
Ramezan Ali Taheri
Keyword(s):  
Klebsiella Pneumoniae ◽  
Dihydrofolate Reductase ◽  
Blood Stream Infection ◽  
Drug Repurposing ◽  
Blood Stream ◽  
New Drugs ◽  
Data Set ◽  
Wide Range ◽  
Approved Drugs ◽  
Dynamics Simulations

Abstract Klebsiella pneumoniae is a gram-negative, non-motile, rod-shaped, and pathogenic bacterium that is widely mutated and resistant to antibiotics. It can cause a wide range of hospital infections such as pneumonia, urinary tract infection, and blood-stream infection in humans. Identification and development of potential drugs due to high drug resistance by Klebsiella pneumoniae are inevitable. Dihydrofolate reductase is a vital enzyme for cells because it converts 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate. Trimethoprim (TMP) is an inhibitor of K. pneumoniae DHFR and other micro-organisms, but resistance to its action develops quickly when it is used. Identifying and designing new drugs is a costly, time-consuming, and challenging process. On the other hand, computational drug repurposing has become an efficient, economical and riskless strategy. In this study, the structure-based virtual docking approach was used to screen the FDA-approved drugs data-set against K. pneumoniae trimethoprim-resistance DHFR to identify potential hit compounds. Then, to validate the hit compounds, molecular dynamics simulations and MM/PBSA analyses were carried out. Our computational drug repurposing results show that the Olodaterol and Pazopanib like reference ligand interact with key residues such as Ile20, Glu27, Phe31, Met50, Leu53 and inhibit K. pneumoniae trimethoprim-resistant dihydrofolate reductase while TMP does not have strong interaction with the active site. According to the results of the current study and since it was based on drug repurposing both compounds of Pazopanib and Olodaterol could be evaluated in phase 2 clinical trials.

scholarly journals Use of Next Generation Sequencing and Synergy Susceptibility Testing in Diagnosis and Treatment of Carbapenem-Resistant Klebsiella pneumoniae Blood Stream Infection

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Yuetian Yu ◽  
Fupin Hu ◽  
Cheng Zhu ◽  
Erzhen Chen ◽  
Liangjing Lu ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Klebsiella Pneumoniae ◽  
Lupus Erythematosus ◽  
Susceptibility Testing ◽  
Blood Stream Infection ◽  
Blood Stream ◽  
Next Generation ◽  
Carbapenem Resistant ◽  
Appropriate Treatment ◽  
Generation Sequencing

Early diagnosis and appropriate treatment for carbapenem-resistant Klebsiella pneumoniae (CR-Kp) infection is a big challenge for clinicians due to its high mortality. Every effort has been made to improve its clinical outcomes. However, treatment according to synergy susceptibility testing has never been reported in the literature. We reported a 29-year-old systemic lupus erythematosus female with CR-Kp blood stream infection. We highlighted the identification by next generation sequencing and treatment according to synergy susceptibility testing in the case.

scholarly journals Repurposing of Linagliptin Similar FDA Approved Drugs as Antidiabetic Agents

2021 ◽  
Vol 10 (4) ◽  
pp. 2766-2776
Keyword(s):  
Metabolic Diseases ◽  
Drug Repurposing ◽  
Binding Energies ◽  
New Drugs ◽  
Epidemic Disease ◽  
Global Epidemic ◽  
Dpp Iv ◽  
Epidemiology Data ◽  
Approved Drugs ◽  
Fda Approved Drugs

Diabetes mellitus is considered a global epidemic disease and is one of the metabolic diseases affecting individuals irrespective of age, sex, and race. According to WHO epidemiology data, the DM prevalence globally has risen from 4.7% to 8.5 % from 1980 to 2014. The discovery of new drugs has become more challenging for the pharmaceutical companies even though major investment has made in the conventional drug discovery approach. To overcome this obstacle, drug repurposing is an emerging field of development where an existing drug is tested for treatment. Successful repurposing of zidovudine, minoxidil, sildenafil, celecoxib, aspirin, and topiramate are reported for respective diseases. The present study focused on the computational approach to fetch the favorable drugs from the pool of FDA approved drugs against diabetes. Initially, structure similarity studies were carried out by using the template structure of standard DPP-IV inhibitor, Linagliptin. About 26 drugs have shown similarity, and the other 14 drugs filtered by Pass Online binding energies are determined by molecular docking at the binding site of DPP-IV (PDB ID 2i78). Among these, pranlukast and mirabegron have shown good binding interactions with dock scores of -13.81 and -13.06.

scholarly journals Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

2020 ◽  
Author(s):  
Catherine Z. Chen ◽  
Paul Shinn ◽  
Zina Itkin ◽  
Richard T. Eastman ◽  
Robert Bostwick ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Treatment Options ◽  
Emerging Infectious Diseases ◽  
Drug Repurposing ◽  
Data Set ◽  
Need For Treatment ◽  
Investigational Drugs ◽  
Compound Collection ◽  
Antiviral Activities ◽  
Approved Drugs

AbstractDrug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.

scholarly journals Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2936
Author(s):  
Leire Dublang ◽  
Jarl Underhaug ◽  
Marte I. Flydal ◽  
Lorea Velasco-Carneros ◽  
Jean-Didier Maréchal ◽  
...  
Keyword(s):  
Functional Gastrointestinal Disorders ◽  
Drug Repurposing ◽  
Melanoma Cancer ◽  
Hsp70 Family ◽  
Wide Range ◽  
Cancer Cell Survival ◽  
Pinaverium Bromide ◽  
Dynamics Simulations ◽  
Resistance To Chemotherapy ◽  
Initial Target

Heat shock protein (Hsp) synthesis is upregulated in a wide range of cancers to provide the appropriate environment for tumor progression. The Hsp110 and Hsp70 families have been associated to cancer cell survival and resistance to chemotherapy. In this study, we explore the strategy of drug repurposing to find new Hsp70 and Hsp110 inhibitors that display toxicity against melanoma cancer cells. We found that the hits discovered using Apg2, a human representative of the Hsp110 family, as the initial target bind also to structural regions present in members of the Hsp70 family, and therefore inhibit the remodeling activity of the Hsp70 system. One of these compounds, the spasmolytic agent pinaverium bromide used for functional gastrointestinal disorders, inhibits the intracellular chaperone activity of the Hsp70 system and elicits its cytotoxic activity specifically in two melanoma cell lines by activating apoptosis. Docking and molecular dynamics simulations indicate that this compound interacts with regions located in the nucleotide-binding domain and the linker of the chaperones, modulating their ATPase activity. Thus, repurposing of pinaverium bromide for cancer treatment appears as a promising novel therapeutic approach.

scholarly journals Differences in Thermal Structural Changes and Melting Between Mesophilic and Thermophilic Dihydrofolate Reductase Enzymes

2020 ◽  
Author(s):  
Irene Maffucci ◽  
Damien Laage ◽  
Guillaume Stirnemann ◽  
Fabio Sterpone
Keyword(s):  
Dihydrofolate Reductase ◽  
Conformational Changes ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Thermotoga Maritima ◽  
Conformational Sampling ◽  
Detailed Understanding ◽  
Wide Range ◽  
The Difference ◽  
Dynamics Simulations

A key aspect of life's evolution on Earth is the adaptation of proteins to be stable and work in a very wide range of temperature conditions. A detailed understanding of the associated molecular mechanisms would also help to design enzymes optimized for biotechnological processes. Despite important advances, a comprehensive picture of how thermophilic enzymes succeed in functioning under extreme temperatures remains incomplete. Here, we examine the temperature dependence of stability and of flexibility in the mesophilic monomeric Escherichia coli (Ec) and thermophilic dimeric Thermotoga maritima (Tm) homologs of the paradigm dihydrofolate reductase (DHFR) enzyme. We use all-atom molecular dynamics simulations and a replica-exchange scheme that allows to enhance the conformational sampling while providing at the same time a detailed understanding of the enzymes' behavior at increasing temperatures. We show that this approach reproduces the stability shift between the two homologs, and provides a molecular description of the denaturation mechanism by identifying the sequence of secondary structure elements melting as temperature increases, which is not straightforwardly obtained in the experiments. By repeating our approach on the hypothetical TmDHFR monomer, we further determine the respective effects of sequence and oligomerization in the exceptional stability of TmDFHR. We show that the intuitive expectation that protein flexibility and thermal stability are correlated is not verified. Finally, our simulations reveal that significant conformational fluctuations already take place much below the melting temperature. While the difference between the TmDHFR and EcDHFR catalytic activities is often interpreted via a simplified two-state picture involving the open and closed conformations of the key M20 loop, our simulations suggest that the two homologs' markedly different activity temperature dependences are caused by changes in the ligand-cofactor distance distributions in response to these conformational changes.

scholarly journals Utilisation of the Prestwick Chemical Library®to identify drugs that inhibit the growth of Mycobacteria

2018 ◽  
Author(s):  
Panchali Kanvatirth ◽  
Rose E. Jeeves ◽  
Joanna Bacon ◽  
Gurdyal S. Besra ◽  
Luke J. Alderwick
Keyword(s):  
Drug Repurposing ◽  
Antimycobacterial Activity ◽  
Drug Regimen ◽  
New Drugs ◽  
Bacterial Disease ◽  
Drug Resistant ◽  
Chemical Library ◽  
Incidence And Mortality ◽  
Approved Drugs ◽  
New Treatments

AbstractTuberculosis (TB) is an infectious bacterial disease that kills approximately 1.3 million people every year. Despite global efforts to reduce both the incidence and mortality associated with TB, the emergence of drug resistant strains has slowed any progress made towards combating the spread of this deadly disease. The current TB drug regimen is inadequate, takes months to complete and poses significant challenges when administering to patients suffering from drug resistant TB. New treatments that are faster, simpler and more affordable are urgently required. Arguably, a good strategy to discover new drugs is to start with an old drug. Here, we have screened a library of 1200 FDA approved drugs from the Prestwick Chemical library®using a GFP microplate assay. Drugs were screened against GFP expressing strains ofMycobacterium smegmatisandMycobacterium bovisBCG as surrogates forMycobacterium tuberculosis,the causative agent of TB in humans. We identified several classes of drugs that displayed antimycobacterial activity against bothM. smegmatisandM. bovisBCG, however each organism also displayed some selectivity towards certain drug classes. Variant analysis of whole genomes sequenced for resistant mutants raised to florfenicol, vanoxerine and pentamidine highlight new pathways that could be exploited in drug repurposing programmes.

scholarly journals Drug Repurposing: A Review

2021 ◽  
pp. 161-169
Author(s):  
Rani Teksinh Bhagat ◽  
Santosh Ramarao Butle
Keyword(s):  
Drug Development ◽  
Research And Development ◽  
Development Process ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
New Drugs ◽  
Preclinical Development ◽  
Therapeutic Uses ◽  
Original Application ◽  
Approved Drugs

The drug development is a very time consuming and complex process. Drug development Process is Expensive. Success rate for the new drug development is very small. In recent years, decreases the new drugs development. The powerful tools are developed to support the research and development (R&D) process is essential. The Drug repurposing are helpful for research and development process. The drug re-purposing as an approach finds new therapeutic uses for current candidates or existing candidates or approved drugs, different from its original application. The main aimed of Drug repurposing is to reduce costs and research time investments in Research & Development. It is used for the diagnosis and treatment of various diseases. Repositioning is important over traditional approaches and need for effective therapies. Drug re-purposing identifies new application for already banned or existing drugs from market. In drug design, drug repurposing plays important role, because it helps to preclinical development. It reducing time efforts, expenses and failures in drug discovery process. It is also called as drug repositioning, drug redirecting, drug reprofiling.

scholarly journals Drug Repurposing in Neurological Diseases: Opportunities and Challenges

2020 ◽  
Author(s):  
Xiao-Yuan Mao
Keyword(s):  
Neurological Diseases ◽  
Drug Repurposing ◽  
New Drugs ◽  
Drug Candidates ◽  
Therapeutic Benefits ◽  
Therapeutic Value ◽  
Traditional Drug ◽  
Approved Drugs ◽  
Structure Complexity ◽  
Refractory Diseases

Drug repurposing or repositioning refers to “studying of clinically approved drugs in one disease to see if they have therapeutic value and do not trigger side effects in other diseases.” Nowadays, it is a vital drug discovery approach to explore new therapeutic benefits of existing drugs or drug candidates in various human diseases including neurological disorders. This approach overcomes the shortage faced during traditional drug development in grounds of financial support and timeline. It is especially hopeful in some refractory diseases including neurological diseases. The feature that structure complexity of the nervous system and influence of blood–brain barrier permeability often becomes more difficult to develop new drugs in neuropathological conditions than diseases in other organs; therefore, drug repurposing is particularly of utmost importance. In this chapter, we discuss the role of drug repurposing in neurological diseases and make a summarization of repurposing candidates currently in clinical trials for neurological diseases and potential mechanisms as well as preliminary results. Subsequently we also outline drug repurposing approaches and limitations and challenges in the future investigations.

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