Covalent Versus Non-covalent Enzyme Inhibition: Which Route Should We Take? A Justification of the Good and Bad from Molecular Modelling Perspective

Aljoundi, Aimen; Bjij, Imane; Rashedy, Ahmed El; Soliman, Mahmoud E. S.

doi:10.1007/s10930-020-09884-2

Cited by 49 publications

(38 citation statements)

References 42 publications

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“… 29 , 30 However, their potential for nonspecific reactivity, toxicity, and undesired side‐effects, rapid in vivo metabolism and reduced oral bioavailability make the irreversible inhibitors less efficient as therapeutic agents. 31 , 32 , 33 , 34 On the other hand, drug repositioning or repurposing is a faster and less costly solution to propose potential effective drugs useful to control emerged infectious outbreaks immediately, as new drug development takes more than 10 years. 35 , 36 Currently, there are no clinically approved therapeutics available.…”

Section: Introductionmentioning

confidence: 99%

Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease

et al. 2021

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The novel coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS‐CoV‐2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (M pro ), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on M pro that can be evaluated as drug targets besides the active site. Then, Food and Drug Administration (FDA)‐approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. Fourteen best molecule hits for the active site of M pro are determined. Six of these also exhibit high docking scores for the potential allosteric regions. Full‐atom molecular dynamics simulations with MM‐GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆ G bind ) values. ∆ G bind values reach −52.06 kcal/mol for the active site, −51.08 kcal/mol for the potential allosteric site 1, and − 42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin, and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as M pro inhibitor candidates to be evaluated against SARS‐CoV‐2 infections.

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Section: Introductionmentioning

confidence: 99%

Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease

et al. 2021

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“…The H-bonds usually confer structural stability and rigidity to the proteinligand complexes. Moreover, there exist Pi-Sigma interactions (Pi-anion, Pi-cation, and Pi-alkyl) and salt bridges that reportedly maximize the binding affinity between protein and ligands in a physiological environment (Rahman et al, 2016;Aljoundi et al, 2020). In the present study, the interaction between tyrosol and target enzymes (TyrRS and CYP51) witnessed some noncovalent forces inclusively H-bonds and Pi-Sigma.…”

Section: Discussionmentioning

confidence: 57%

Isolation and Characterization of an Endophytic Fungus Colletotrichum coccodes Producing Tyrosol From Houttuynia cordata Thunb. Using ITS2 RNA Secondary Structure and Molecular Docking Study

Talukdar

Padhi

Kumar

et al. 2021

Front. Bioeng. Biotechnol.

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An endophytic fungus isolated from healthy leaf tissues of Houttuynia cordata Thunb., an ethnomedicinal plant of North East India, showed a considerable amount of antimicrobial activity. The ethyl acetate extract of the fungal culture filtrates displayed promising antimicrobial activity against a panel of clinically significant pathogens including Candida albicans, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Bioassay guided purification of the organic extract using column and thin layer chromatography yielded a pure homogenous compound which was identified using spectroscopic methods (essentially by 1H NMR and MS) as tyrosol, a well-known phenylethanoid present in several natural sources. Besides, molecular docking studies against tyrosyl tRNA synthetases (TyrRS) of S. aureus (PDB ID: 1JIL) and E. coli (PDB ID: 1VBM), and CYP45014α-lanosterol demethylase (CYP51) of C. albicans (PDB ID: 5FSA) revealed tyrosol has a strong binding affinity with the enzyme active site residues. The fungus was identified as Colletotrichum sp. and characterized by its genomic ITS rDNA and ITS2 sequences. Phylogenetic analyses showed clustering of our isolate with Colletotrichum coccodes. Species of Colletotrichum are also reported to be plant pathogens. Therefore, to confirm the endophytic lifestyle of the isolate, ITS2 RNA secondary structure study was undertaken. The result indicated our isolate exhibited differences in the folding pattern as well as in motif structures when compared to those of pathogenic C. coccodes. The findings indicated that endophytic fungi harboring H. cordata could be explored as a potent source of antimicrobial agents.

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“…The protein-ligand interaction is mainly governed by two major forces, the covalent and noncovalent interactions. The covalent inhibitors are generally not preferred for drug development programme because of their expected toxicity resulting from non-specific inhibition of intracellular enzymes and proteins involved in the normal cellular functioning [40]. In present study, although the tested compounds were evaluated only for the noncovalent interactions with the target proteins, their involvement in establishing covalent interactions with the target proteins cannot be ignored.…”

Section: Discussionmentioning

confidence: 99%

In Silico Investigation on the Binding of Organoselenium Compounds with Target Proteins of SARS-CoV-2 Infection Cycle

Gobind¹,

Singh

Kunwar³

2020

Preprint

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Since the outbreak of coronavirus disease 2019 (COVID-19), researchers have been investigating the potential of several low molecular weight compounds from both natural and synthetic origins to design anti-viral drugs against SARS-CoV-2. On similar lines, the present study is aimed to evaluate different organoselenium compounds and their sulfur analogues by using a molecular docking approach to inhibit viral proteins like spike (S) glycoprotein (PDB code: 6VXX) and main protease (Mpro) (PDB code: 6LU7) and a host protein, Furin (PDB code: 5MIM), all of which are known to play significant role in SARS-CoV-2 infection cycle. The organoselenium compounds used in the study are mostly in-house synthesized including simple selenium containing amino acids and their derivatives and selenopyridines and their derivatives. The docking calculations were performed using AutoDock Vina. In brief, organoselenium compounds showed stronger binding with the target proteins as compared to their sulfur analogue, except oxidized glutathione. Notably, the most potent docked ligands shared a common structural feature of aromatic amide moieties connected by diselenide bridge. Further, the compounds ebselen diselenide (EbSeSeEb) and nicotinamide diselenide (NictSeSeNict) exhibited the highest binding affinity (in range of ~105 µM-1) to all the above three proteins. Thus, the present investigation highlights the influence of structure and substitution of organoselenium compound on their binding with the SARS-CoV-2 proteins and proposes NictSeSeNict as a candidate molecule for evaluating anti-viral activity against SARS-CoV-2 using preclinical biological models.

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Covalent Versus Non-covalent Enzyme Inhibition: Which Route Should We Take? A Justification of the Good and Bad from Molecular Modelling Perspective

Cited by 49 publications

References 42 publications

Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease

Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease

Isolation and Characterization of an Endophytic Fungus Colletotrichum coccodes Producing Tyrosol From Houttuynia cordata Thunb. Using ITS2 RNA Secondary Structure and Molecular Docking Study

In Silico Investigation on the Binding of Organoselenium Compounds with Target Proteins of SARS-CoV-2 Infection Cycle

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