hiv protease inhibitors
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Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7385
Author(s):  
Wei Yu ◽  
Xiaomin Wu ◽  
Yizhen Zhao ◽  
Chun Chen ◽  
Zhiwei Yang ◽  
...  

SARS-CoV-2 is highly homologous to SARS-CoV. To date, the main protease (Mpro) of SARS-CoV-2 is regarded as an important drug target for the treatment of Coronavirus Disease 2019 (COVID-19). Some experiments confirmed that several HIV protease inhibitors present the inhibitory effects on the replication of SARS-CoV-2 by inhibiting Mpro. However, the mechanism of action has still not been studied very clearly. In this work, the interaction mechanism of four HIV protease inhibitors Darunavir (DRV), Lopinavir (LPV), Nelfinavir (NFV), and Ritonavire (RTV) targeting SARS-CoV-2 Mpro was explored by applying docking, molecular dynamics (MD) simulations, and MM–GBSA methods using the broad-spectrum antiviral drug Ribavirin (RBV) as the negative and nonspecific control. Our results revealed that LPV, RTV, and NFV have higher binding affinities with Mpro, and they all interact with catalytic residues His41 and the other two key amino acids Met49 and Met165. Pharmacophore model analysis further revealed that the aromatic ring, hydrogen bond donor, and hydrophobic group are the essential infrastructure of Mpro inhibitors. Overall, this study applied computational simulation methods to study the interaction mechanism of HIV-1 protease inhibitors with SARS-CoV-2 Mpro, and the findings provide useful insights for the development of novel anti-SARS-CoV-2 agents for the treatment of COVID-19.


2021 ◽  
Vol 9 (12) ◽  
pp. 2481
Author(s):  
Rafida Razali ◽  
Haslina Asis ◽  
Cahyo Budiman

The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is considered the greatest challenge to the global health community of the century as it continues to expand. This has prompted immediate urgency to discover promising drug targets for the treatment of COVID-19. The SARS-CoV-2 viral proteases, 3-chymotrypsin-like protease (3CLpro) and papain-like cysteine protease (PLpro), have become the promising target to study due to their essential functions in spreading the virus by RNA transcription, translation, protein synthesis, processing and modification, virus replication, and infection of the host. As such, understanding of the structure and function of these two proteases is unavoidable as platforms for the development of inhibitors targeting this protein which further arrest the infection and spread of the virus. While the abundance of reports on the screening of natural compounds such as SARS-CoV-2 proteases inhibitors are available, the microorganisms-based compounds (peptides and non-peptides) remain less studied. Indeed, microorganisms-based compounds are also one of the potent antiviral candidates against COVID-19. Microbes, especially bacteria and fungi, are other resources to produce new drugs as well as nucleosides, nucleotides, and nucleic acids. Thus, we have compiled various reported literature in detail on the structures, functions of the SARS-CoV-2 proteases, and potential inhibitors from microbial sources as assistance to other researchers working with COVID-19. The compounds are also compared to HIV protease inhibitors which suggested the microorganisms-based compounds are advantageous as SARS-CoV2 proteases inhibitors. The information should serve as a platform for further development of COVID-19 drug design strategies.


Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1620
Author(s):  
Dharmendra Kumar Yadav ◽  
Desh Deepak Singh ◽  
Ihn Han ◽  
Yogesh Kumar ◽  
Eun-Ha Choi

The ongoing SARS-CoV-2 pandemic is a serious threat to public health worldwide and, to date, no effective treatment is available. Thus, we herein review the pharmaceutical approaches to SARS-CoV-2 infection treatment. Numerous candidate medicines that can prevent SARS-CoV-2 infection and replication have been proposed. These medicines include inhibitors of serine protease TMPRSS2 and angiotensin converting enzyme 2 (ACE2). The S protein of SARS-CoV-2 binds to the receptor in host cells. ACE2 inhibitors block TMPRSS2 and S protein priming, thus preventing SARS-CoV-2 entry to host cells. Moreover, antiviral medicines (including the nucleotide analogue remdesivir, the HIV protease inhibitors lopinavir and ritonavir, and wide-spectrum antiviral antibiotics arbidol and favipiravir) have been shown to reduce the dissemination of SARS-CoV-2 as well as morbidity and mortality associated with COVID-19.


2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shaheen Begum ◽  
Mohammad Zubair Shareef ◽  
Koganti Bharathi

Abstract In silico tools have indeed reframed the steps involved in traditional drug discovery and development process and the term in silico has become a familiar term in pharmaceutical sector like the terms in vitro and in vivo. The successful design of HIV protease inhibitors, Saquinavir, Indinavir and other important medicinal agents, initiated interest of researchers in structure based drug design approaches (SBDD). The interactions between biomolecules and a ligand, binding energy, free energy and stability of biomolecule-ligand complex can be envisioned and predicted by applying molecular docking studies. Protein-ligand, protein-protein, DNA-ligand interactions etc. aid in elucidating molecular level mechanisms of drug molecules. In the Ligand based drug design (LBDD) approaches, QSAR studies have tremendously contributed to the development of antimicrobial, anticancer, antimalarial agents. In the recent years, multiQSAR (mt-QSAR) approaches have been successfully employed for designing drugs against multifactorial diseases. Output of a research in several instances is rewarding when both SBDD and LBDD approaches are combined. Application of in silico studies for prediction of pharmacokinetics was once a real challenge but one can see unlimited number publications comprising tools, data bases which can accurately predict almost all the pharmacokinetic parameters. Absorption, distribution, metabolism, transporters, blood brain barrier permeability, hERG toxicity, P-gp affinity and several toxicological end points can be accurately predicted for a candidate molecule before its synthesis. In silico approaches are greatly encouraged a result of growing limitations and new legislations related to the animal use for research. The combined use of in vitro data and in silico tools will definitely decrease the use of animal testing in the future.In this chapter, in silico approaches and their applications are reviewed and discussed giving suitable examples.


2021 ◽  
Author(s):  
Monisha Mohan ◽  
Roy Anindya

ABSTRACTThe human DNA repair enzyme AlkB homologue-2 and 3 (ALKBH2 and ALKKBH3) repairs methyl adducts from genomic DNA. Overexpression of ALKBH2 and ALKBH3 has been implicated in both tumorigenesis and chemotherapy resistance in some cancers, including glioblastoma and renal cancer rendering it a potential therapeutic target and a diagnostic marker. However, no inhibitor is available against these important DNA repair proteins. Intending to repurpose a drug as an inhibitor of ALKBH2/ALKBH3, we performed in silico evaluation of HIV protease inhibitors and identified Ritonavir as an ALKBH2-interacting molecule. Using molecular dynamics simulation, we elucidated the molecular details of Ritonavir-ALKBH2 interaction. The present work highlights that Ritonavir might be used to target the ALKBH2-mediated DNA alkylation repair.


2021 ◽  
Vol 72 (1) ◽  
pp. 1-8
Author(s):  
Linh Tran ◽  
Dao Ngoc Hien Tam ◽  
Heba Elhadad ◽  
Nguyen Minh Hien ◽  
Nguyen Tien Huy

Abstract The epidemic of the novel coronavirus disease (COVID-19) that started in 2019 has evoked an urgent demand for finding new potential therapeutic agents. In this study, we performed a molecular docking of anti-HIV drugs to refine HIV protease inhibitors and nucleotide analogues to target COVID-19. The evaluation was based on docking scores calculated by AutoDock Vina and top binding poses were analyzed. Our results suggested that lopinavir, darunavir, atazanavir, remdesivir, and tipranavir have the best binding affinity for the 3-chymotrypsin-like protease of COVID-19. The comparison of the binding sites of three drugs, namely, darunavir, atazanavir and remdesivir, showed an overlap region of the protein pocket. Our study showed a strong affinity between lopinavir, darunavir, atazanavir, tipranavir and COVID-19 protease. However, their efficacy should be confirmed by in vitro studies since there are concerns related to interference with their active sites.


2021 ◽  
Vol 13 (607) ◽  
pp. eabd3904
Author(s):  
Zachary F. Caffall ◽  
Bradley J. Wilkes ◽  
Ricardo Hernández-Martinez ◽  
Joseph E. Rittiner ◽  
Jennifer T. Fox ◽  
...  

Dystonias are a group of chronic movement–disabling disorders for which highly effective oral medications or disease-modifying therapies are lacking. The most effective treatments require invasive procedures such as deep brain stimulation. In this study, we used a high-throughput assay based on a monogenic form of dystonia, DYT1 (DYT-TOR1A), to screen a library of compounds approved for use in humans, the NCATS Pharmaceutical Collection (NPC; 2816 compounds), and identify drugs able to correct mislocalization of the disease-causing protein variant, ∆E302/3 hTorsinA. The HIV protease inhibitor, ritonavir, was among 18 compounds found to normalize hTorsinA mislocalization. Using a DYT1 knock-in mouse model to test efficacy on brain pathologies, we found that ritonavir restored multiple brain abnormalities across development. Ritonavir acutely corrected striatal cholinergic interneuron physiology in the mature brain and yielded sustained correction of diffusion tensor magnetic resonance imaging signals when delivered during a discrete early developmental window. Mechanistically, we found that, across the family of HIV protease inhibitors, efficacy correlated with integrated stress response activation. These preclinical results identify ritonavir as a drug candidate for dystonia with disease-modifying potential.


2021 ◽  
Vol Volume 13 ◽  
pp. 789-800
Author(s):  
Gerrit Kann ◽  
Junaid Owasil ◽  
Karina Kuczka ◽  
Annette Haberl ◽  
Timo Wolf ◽  
...  

2021 ◽  
Author(s):  
Matthew D. Lloyd

Steady-state enzyme kinetics is a cornerstone technique of biochemistry and related sciences since it allows the characterization and quantification of enzyme behaviour. Enzyme kinetics is widely used to investigate the physiological role of enzymes, determine the effects of mutations and characterize enzyme inhibitors. Well-known examples of enzyme inhibitors used to treat diseases include anti-infectives (e.g., penicillin, clavulanic acid and HIV protease inhibitors); anti-inflammatories (e.g., aspirin and ibuprofen); cholesterol-lowering statins; tyrosine kinase inhibitors used to treat cancer; and Viagra. Commonly, new disease treatments are discovered by using enzyme kinetics to identify the few active compounds residing within a large compound collection (‘high-throughput screening’). The subject of enzyme kinetics is typically introduced to first-year undergraduates with a mathematical description of behaviour. This Beginners Guide will give a brief overview of experimental enzyme kinetics and the characterization of enzyme inhibitors. Colorimetric assays using a microtitre plate will be considered, although most principles also apply to other assays.


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