Comparison of irreversible inhibition targeting HSP72 protein: the resurgence of covalent drug developments

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

doi:10.1080/08927022.2021.1949457

Cited by 3 publications

(3 citation statements)

References 45 publications

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“…We believe that a concise technical guide on each challenge and a list of potential solutions would be helpful to researchers working on improving docking protocols (Table 2). These guidelines are primarily based on our experience we have accumulated over the years in covalent docking research [23][24][25][26][27][28][29] .…”

Section: Flexible Protein-peptide Docking Methods -A Way Forwardmentioning

confidence: 99%

“…Although significant efforts have been made to aid the modelling and design of noncovalent peptides, the molecular simulations of covalent peptide interactions remain a challenging task, especially with the lack of peptide-specific validated protocol that takes into account covalent binding between the peptide and the receptor [18,[20][21][22] . Along with our earlier reports on covalent docking [23][24][25][26][27][28][29] , The current report will concentrate on covalent peptide docking, its challenges, and provide potential solutions including technical guidance to useful tools and approaches to assist with the rational design of covalent peptide inhibitors.…”

Section: Small Molecules Inhibitors Vs Peptides -Evolution Of Covalen...mentioning

confidence: 99%

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Covalent Flexible Peptide Docking in Drug Discovery: Current Challenges and Potential Interventions

Lafifi,

Bjij,

Soliman

2024

Innov Discov

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Recently, there has been a significant increase in the search for new covalent inhibitors through drug discovery platforms, which has led to the development and implementation of new computational tools, including covalent docking methods to predict the binding mode and affinity of covalent ligands. Since the discovery of insulin nearly a century ago, more than 80 peptide medications have hit the market to treat a wide range of diseases, including diabetes, cancer, osteoporosis, multiple sclerosis, HIV infection, and chronic pain. Electrophilic peptides that form covalent bonds with target proteins have great potential for binding targets that have been previously considered undruggable. Despite the recent advancements in computational performance and docking algorithms, covalent docking still poses a number of challenges. Peptides covalent docking presents additional challenges, the main ones being the choice of the optimal peptide sequence, incorporation of electrophilic warheads, the inherent flexibility of peptide structures, and the fact that, unlike small molecules, peptides do fold. In this review, we present a brief overview of the current state of peptide therapeutics in drug discovery, covalent docking in general, covalent peptide binders, and-with particular emphasis-the difficulties that covalent peptide-protein docking is currently facing and some potential solutions.

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Section: Flexible Protein-peptide Docking Methods -A Way Forwardmentioning

confidence: 99%

Section: Small Molecules Inhibitors Vs Peptides -Evolution Of Covalen...mentioning

confidence: 99%

Covalent Flexible Peptide Docking in Drug Discovery: Current Challenges and Potential Interventions

Lafifi,

Bjij,

Soliman

2024

Innov Discov

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show abstract

“…MD simulations were carried out to investigate the inhibition performance and interactions of the potential eight ligands with BS1 and BS2. Validation of system stability and flexibility is essential for tracing disrupted motions and avoiding artifacts that may arise during the course of the simulation [ 33 , 34 ]. In this study, root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) were calculated to measure the systems’ stability and flexibility during the 100 ns simulations [ 35 , 36 ].…”

Section: Dynamic Conformational Stability and Fluctuationsmentioning

confidence: 99%

The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)’s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19

et al. 2023

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The unusual and interesting architecture of the catalytic chamber of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) was recently explored using Cryogenic Electron Microscopy (Cryo-EM), which revealed the presence of two distinctive binding cavities within the catalytic chamber. In this report, first, we mapped out and fully characterized the variations between the two binding sites, BS1 and BS2, for significant differences in their amino acid architecture, size, volume, and hydrophobicity. This was followed by investigating the preferential binding of eight antiviral agents to each of the two binding sites, BS1 and BS2, to understand the fundamental factors that govern the preferential binding of each drug to each binding site. Results showed that, in general, hydrophobic drugs, such as remdesivir and sofosbuvir, bind better to both binding sites than relatively less hydrophobic drugs, such as alovudine, molnupiravir, zidovudine, favilavir, and ribavirin. However, suramin, which is a highly hydrophobic drug, unexpectedly showed overall weaker binding affinities in both binding sites when compared to other drugs. This unexpected observation may be attributed to its high binding solvation energy, which disfavors overall binding of suramin in both binding sites. On the other hand, hydrophobic drugs displayed higher binding affinities towards BS1 due to its higher hydrophobic architecture when compared to BS2, while less hydrophobic drugs did not show a significant difference in binding affinities in both binding sites. Analysis of binding energy contributions revealed that the most favorable components are the ΔEele, ΔEvdw, and ΔGgas, whereas ΔGsol was unfavorable. The ΔEele and ΔGgas for hydrophobic drugs were enough to balance the unfavorable ΔGsol, leaving the ΔEvdw to be the most determining factor of the total binding energy. The information presented in this report will provide guidelines for tailoring SARS-CoV-2 inhibitors with enhanced binding profiles.

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Implication of Ab Initio, QM/MM, and molecular dynamics calculations on the prediction of the therapeutic potential of some selected HDAC inhibitors

Dushanan

Weerasinghe

Dissanayake

et al. 2022

Molecular Simulation

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Comparison of irreversible inhibition targeting HSP72 protein: the resurgence of covalent drug developments

Cited by 3 publications

References 45 publications

Covalent Flexible Peptide Docking in Drug Discovery: Current Challenges and Potential Interventions

Covalent Flexible Peptide Docking in Drug Discovery: Current Challenges and Potential Interventions

The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)’s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19

Implication of Ab Initio, QM/MM, and molecular dynamics calculations on the prediction of the therapeutic potential of some selected HDAC inhibitors

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