Perspectives on SARS-CoV-2 Main Protease Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(23), P. 16922 - 16955

Published: Nov. 19, 2021

The main protease (Mpro) plays a crucial role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and is highly conserved, rendering it one of the most attractive therapeutic targets for SARS-CoV-2 inhibition. Currently, although two drug candidates targeting Mpro designed by Pfizer are under clinical trials, no medication approved due to long period development. Here, we collect comprehensive list 817 available SARS-CoV inhibitors from literature or databases analyze their molecular mechanisms action. structure–activity relationships (SARs) among each series discussed. Additionally, broadly examine antiviral activity, ADMET (absorption, distribution, metabolism, excretion, toxicity), animal tests these inhibitors. We comment on druggability drawbacks that prevent them becoming drugs. This Perspective sheds light future development diseases.

Language: Английский

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An Effective MM/GBSA Protocol for Absolute Binding Free Energy Calculations: A Case Study on SARS-CoV-2 Spike Protein and the Human ACE2 Receptor

Molecules, Journal Year: 2021, Volume and Issue: 26(8), P. 2383 - 2383

Published: April 20, 2021

The binding free energy calculation of protein-ligand complexes is necessary for research into virus-host interactions and the relevant applications in drug discovery. However, many current computational methods such calculations are either inefficient or inaccurate practice. Utilizing implicit solvent models molecular mechanics generalized Born surface area (MM/GBSA) framework allows efficient without significant loss accuracy. Here, GBNSR6, a new flavor model, employed MM/GBSA measuring affinity between SARS-CoV-2 spike protein human ACE2 receptor. A protocol developed based on widely studied Ras-Raf complex, which has similar to SARS-CoV-2/ACE2. Two options representing dielectric boundary evaluated: one standard Bondi radii other newly set atomic (OPT1), optimized specifically binding. Predictions two sets provide upper lower bounds experimental references: -14.7(ΔGbindBondi)<-10.6(ΔGbindExp.)<-4.1(ΔGbindOPT1) kcal/mol. consensus estimates show quantitative agreement with experiment values. This work also presents novel truncation method strategies entropy normal mode analysis. Interestingly, it observed that decrease number snapshots does not affect accuracy calculation, while computation time appreciably. proposed can be used study mechanism variants SARS-CoV-2, as well structures.

Language: Английский

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Green and efficient one-pot three-component synthesis of novel drug-like furo[2,3-d]pyrimidines as potential active site inhibitors and putative allosteric hotspots modulators of both SARS-CoV-2 MPro and PLPro

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 135, P. 106390 - 106390

Published: Jan. 28, 2023

Language: Английский

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Reviewing methods of deep learning for diagnosing COVID-19, its variants and synergistic medicine combinations

Computers in Biology and Medicine, Journal Year: 2023, Volume and Issue: 163, P. 107191 - 107191

Published: June 20, 2023

Language: Английский

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SARS-CoV-2 Omicron Subvariants Do Not Differ Much in Binding Affinity to Human ACE2: A Molecular Dynamics Study

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(14), P. 3340 - 3349

Published: April 2, 2024

The emergence of the variant concern Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exacerbates COVID-19 pandemic due to its high contagious ability. Studies have shown that binds human ACE2 more strongly than wild type. prevalence in new cases promotes novel lineages with improved receptor binding affinity and immune evasion. To shed light on this open problem, work, we investigated free energy domain BA.2, BA.2.3.20, BA.3, BA4/BA5, BA.2.75, BA.2.75.2, BA.4.6, XBB.1, XBB.1.5, BJ.1, BN.1, BQ.1.1, CH.1.1 using all-atom molecular dynamics simulation mechanics Poisson–Boltzmann surface area method. results show these increased compared BA.1 lineage, BA.2.75 BA.2.75.2 subvariants bind others. However, general, affinities do not differ significantly from each other. electrostatic force dominates over van der Waals interaction between cells. Based our results, argue viral evolution does further improve SARS-CoV-2 for but may increase

Language: Английский

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Biophysics of SARS-CoV-2 spike protein’s receptor-binding domain interaction with ACE2 and neutralizing antibodies: from computation to functional insights

Biophysical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: March 8, 2025

Language: Английский

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Conformational Stability and Denaturation Processes of Proteins Investigated by Electrophoresis under Extreme Conditions

Molecules, Journal Year: 2022, Volume and Issue: 27(20), P. 6861 - 6861

Published: Oct. 13, 2022

The functional structure of proteins results from marginally stable folded conformations. Reversible unfolding, irreversible denaturation, and deterioration can be caused by chemical physical agents due to changes in the physicochemical conditions pH, ionic strength, temperature, pressure, electric field or presence a cosolvent that perturbs delicate balance between stabilizing destabilizing interactions eventually induces modifications. For most proteins, denaturation is complex process involving transient intermediates several reversible steps. Knowledge protein stability processes mandatory for development enzymes as industrial catalysts, biopharmaceuticals, analytical medical bioreagents, safe food. Electrophoresis techniques operating under extreme are convenient tools analyzing unfolding transitions, trapping intermediates, gaining insight into mechanisms processes. Moreover, quantitative analysis electrophoretic mobility transition curves allows estimation conformational proteins. These approaches include polyacrylamide gel electrophoresis capillary zone cold, heat, hydrostatic pressure non-ionic denaturing stabilizers such polyols heavy water. Lastly, after exposure extremes conditions, standard provides information on processes, slow drifts, renaturation impressive developments enzyme technology with multiple applications fine chemistry, biopharmaceutics, nanomedicine prompted us revisit potentialities these approaches. This feature review illustrated published unpublished obtained authors cholinesterases paraoxonase, two physiologically toxicologically important enzymes.

Language: Английский

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SARS-CoV-2 Omicron Variant Binds to Human Cells More Strongly than the Wild Type: Evidence from Molecular Dynamics Simulation

The Journal of Physical Chemistry B, Journal Year: 2022, Volume and Issue: 126(25), P. 4669 - 4678

Published: June 20, 2022

The emergence of the variant concern Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 has aggravated Covid-19 pandemic due to its very contagious ability. high infection rate may be binding affinity human cells, but both experimental and computational studies have yielded conflicting results on this issue. Some shown that binds angiotensin-converting enzyme (hACE2) more strongly than wild type (WT), other reported comparable affinities. To shed light open problem, in work, we calculated free energy receptor domain (RBD) WT spike protein hACE2 using all-atom molecular dynamics simulation mechanics Poisson-Boltzmann surface area method. We showed cells increased RBD charge, which enhances electrostatic interaction with negatively charged hACE2. N440K, T478K, E484A, Q493R, Q498R mutations been found play a critical role stability RBD-hACE2 complex. effect homogeneous heterogeneous models glycans coating viral peptidyl was examined. Although total is not sensitive glycan model, distribution per-residue energies depends it. In addition, little

Language: Английский

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Electrostatic Features for the Receptor Binding Domain of SARS-COV-2 Wildtype and Its Variants. Compass to the Severity of the Future Variants with the Charge-Rule

The Journal of Physical Chemistry B, Journal Year: 2022, Volume and Issue: 126(36), P. 6835 - 6852

Published: Sept. 6, 2022

Electrostatic intermolecular interactions are important in many aspects of biology. We have studied the main electrostatic features involved interaction receptor-binding domain (RBD) SARS-CoV-2 spike protein with human receptor Angiotensin-converting enzyme 2 (ACE2). As principal computational tool, we used FORTE approach, capable to model proton fluctuations and computing free energies for a very large number protein–protein systems under different physical–chemical conditions, here focusing on RBD-ACE2 interactions. Both wild-type all critical variants included this study. From our ensemble extensive simulations, obtain, as function pH, binding affinities, charges proteins, their charge regulation capacities, dipole moments. In addition, calculated pKas ionizable residues mapped coupling between them. able present simple predictor based data obtained Alpha, Beta, Gamma, Delta, Omicron variants, linear correlation total RBD corresponding affinity. This "RBD rule" should work quick test degree severity coming future.

Language: Английский

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The current science of sequence-defined macromolecules

Progress in Polymer Science, Journal Year: 2023, Volume and Issue: 147, P. 101754 - 101754

Published: Oct. 20, 2023

A fundamental endeavour in macromolecular science is the control of molecular-level complexity, including molecular weight distribution, end groups and architecture. Since discovery that native biomacromolecules can have a specific sequence translating biological function, controlling individual monomer has become ultimate expression complexity. Replicating this remarkable structural precision abiological macromolecules emerged as defining goal challenge within polymer science. In Review, we survey developments synthetic methods, characterisation techniques, simulation workflows applications relevant to goal. We also address broader question what extent such complexity significant macromolecules. Specifically, will focus on Review because its importance connecting synthesis with applications.

Language: Английский

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