A critical overview of computational approaches employed for COVID-19 drug discovery

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 50(16), P. 9121 - 9151

Published: Jan. 1, 2021

COVID-19 has resulted in huge numbers of infections and deaths worldwide brought the most severe disruptions to societies economies since Great Depression. Massive experimental computational research effort understand characterize disease rapidly develop diagnostics, vaccines, drugs emerged response this devastating pandemic more than 130 000 COVID-19-related papers have been published peer-reviewed journals or deposited preprint servers. Much focused on discovery novel drug candidates repurposing existing against COVID-19, many such projects either exclusively computer-aided studies. Herein, we provide an expert overview key methods their applications for small-molecule therapeutics that reported literature. We further outline that, after first year pandemic, it appears not produced rapid global solutions. However, several known used clinic cure patients, a few repurposed continue be considered clinical trials, along with candidates. posit truly impactful tools must deliver actionable, experimentally testable hypotheses enabling combinations, open science sharing results are critical accelerate development novel, much needed COVID-19.

Language: Английский

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Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(13), P. 11287 - 11368

Published: May 20, 2022

Despite tremendous efforts in the past two years, our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus-host interactions, immune response, virulence, transmission, and evolution is still very limited. This limitation calls for further in-depth investigation. Computational studies have become an indispensable component combating disease 2019 (COVID-19) due to their low cost, efficiency, fact that they are free from safety ethical constraints. Additionally, mechanism governs global transmission SARS-CoV-2 cannot be revealed individual experiments was discovered by integrating genotyping massive viral sequences, biophysical modeling protein-protein deep mutational data, learning, advanced mathematics. There exists a tsunami literature on molecular modeling, simulations, predictions related developments drugs, vaccines, antibodies, diagnostics. To provide readers with quick update about this literature, we present comprehensive systematic methodology-centered review. Aspects such as biophysics, bioinformatics, cheminformatics, machine mathematics discussed. review will beneficial researchers who looking ways contribute those interested status field.

Language: Английский

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Neuroimmune nexus in the pathophysiology and therapy of inflammatory disorders: Role of α7 nicotinic acetylcholine receptors

Pharmacological Research, Journal Year: 2023, Volume and Issue: 191, P. 106758 - 106758

Published: April 5, 2023

The α7-nicotinic acetylcholine receptor (α7nAChR) is a key protein in the cholinergic anti-inflammatory pathway (CAP) that links nervous and immune systems. Initially, was discovered based on observation vagal nerve stimulation (VNS) reduced systemic inflammatory response septic animals. Subsequent studies form foundation for leading hypothesis about central role of spleen CAP activation. VNS evokes noradrenergic ACh release from T cells spleen, which turn activates α7nAChRs surface macrophages. α7nAChR-mediated signaling macrophages reduces cytokine secretion modifies apoptosis, proliferation, macrophage polarization, eventually reducing response. A protective has been demonstrated preclinical multiple diseases including sepsis, metabolic disease, cardiovascular diseases, arthritis, Crohn's ulcerative colitis, endometriosis, potentially COVID-19, sparking interest using bioelectronic pharmacological approaches to target treating conditions patients. Despite keen interest, many aspects are still unknown. expressed other subsets can affect development inflammation differently. There also sources modify cell functions. How interplay α7nAChR different various tissues contributes responses requires additional study. This review provides an update basic translational relevant pharmacology α7nAChR-activated drugs raises some questions require further investigation.

Language: Английский

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SARS-CoV-2 spike ectodomain targets α7 nicotinic acetylcholine receptors

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(5), P. 104707 - 104707

Published: April 13, 2023

Virus entry into animal cells is initiated by attachment to target macromolecules located on host cells. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) trimeric spike glycoprotein targets angiotensin converting enzyme gain cellular access. SARS-CoV-2 contains a neurotoxin-like region that has sequence similarities the rabies virus and HIV glycoproteins, as well snake neurotoxins, which interact with nicotinic acetylcholine receptor (nAChR) subtypes via this region. Using peptide of (SARS-CoV-2 [SCoV2P]), we identified area moderately inhibits α3β2, α3β4, α4β2 subtypes, while potentiating inhibiting α7 nAChRs. These nAChR are found in tissues including nose, lung, central nervous system, immune Importantly, SCoV2P potentiates ACh-induced responses an allosteric mechanism, nicotine enhancing these effects. Live-cell confocal microscopy was used confirm interacts nAChRs transfected neuronal-like N2a human embryonic kidney 293 ectodomain functionally subtype nanomolar potency. Our functional findings identify for glycoprotein, providing new aspect our understanding cell interactions, addition disease pathogenesis.

Language: Английский

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Characterization of Structural and Energetic Differences between Conformations of the SARS-CoV-2 Spike Protein

Materials, Journal Year: 2020, Volume and Issue: 13(23), P. 5362 - 5362

Published: Nov. 26, 2020

The novel coronavirus disease 2019 (COVID-19) pandemic has disrupted modern societies and their economies. resurgence in COVID-19 cases as part of the second wave is observed across Europe Americas. scientific response enabled a complete structural characterization Severe Acute Respiratory Syndrome-novel Coronavirus 2 (SARS-CoV-2). Among most relevant proteins required by to facilitate cell entry mechanism spike protein. This protein possesses receptor-binding domain (RBD) that binds cellular angiotensin-converting enzyme (ACE2) then triggers fusion viral host membranes. In this regard, comprehensive stability crucial step find new therapeutics interrupt process recognition. On other hand, it been suggested participation more than one RBD possible enhance entry. Here, we discuss based on computational determination dynamic contact map energetic difference conformations via mapping hydration free energy Poisson-Boltzmann method. We expect our result foster discussion number involved during recognition repurposing drugs disable discovering hotspots for drug targets apart from flexible loop ACE2.

Language: Английский

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Large variation in anti-SARS-CoV-2 antibody prevalence among essential workers in Geneva, Switzerland

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 8, 2021

Abstract Limited data exist on SARS-CoV-2 infection rates across sectors and occupations, hindering our ability to make rational policy, including vaccination prioritization, protect workers limit spread. Here, we present results from SEROCoV-WORK + study, a serosurvey of recruited after the first wave COVID-19 pandemic in Geneva, Switzerland. We tested (May 18—September 18, 2020) 16 32 occupations for anti-SARS-CoV-2 IgG antibodies. Of 10,513 participants, 1026 (9.8%) positive. The seropositivity rate ranged 4.2% media sector 14.3% nursing home sector. found considerable within-sector variability: (0%–31.4%), homecare (3.9%–12.6%), healthcare (0%–23.5%), public administration (2.6%–24.6%), security (0%–16.7%). Seropositivity also varied 15.0% among kitchen staff 14.4% nurses, 5.4% domestic care 2.8% journalists. Our findings show that widely sectors, between facilities within reflecting higher exposure certain occupations.

Language: Английский

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α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6524 - 6524

Published: March 30, 2023

Nicotinic acetylcholine receptors (nAChRs) present as many different subtypes in the nervous and immune systems, muscles on cells of other organs. In system, inflammation is regulated via vagus nerve through activation non-neuronal α7 nAChR subtype, affecting production cytokines. The analgesic properties nAChR-selective compounds are mostly based cholinergic anti-inflammatory pathway. molecular mechanism neuropathic pain relief mediated by inhibition α9-containing nAChRs not fully understood yet, but role factors this process becoming evident. To obtain appropriate drugs, a search selective agonists, antagonists modulators α7- underway. naturally occurring three-finger snake α-neurotoxins mammalian Ly6/uPAR proteins, well neurotoxic peptides α-conotoxins, only sophisticated tools research also considered potential medicines. particular, α-conotoxins may be pathway to alleviate pain. involved processes during AIDS viral infections; thus they can means used drug design. review, we discuss

Language: Английский

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COVID-19 Modified mRNA “Vaccines”: Lessons Learned from Clinical Trials, Mass Vaccination, and the Bio-Pharmaceutical Complex, Part 1

International Journal of Vaccine Theory Practice and Research, Journal Year: 2024, Volume and Issue: 3(2), P. 1112 - 1178

Published: June 29, 2024

Our understanding of COVID-19 synthetic, modified mRNA (modmRNA) products and their public health impact has evolved substantially since December 2020. Published reports from the original randomized placebo-controlled trials concluded that modmRNA injections could greatly reduce symptoms. However, premature termination both obviated any reliable assessment potential adverse events due to an insufficient timeframe for proper safety evaluation. Following authorization global distribution, problems with methods execution have emerged. The usual testing protocols toxicology requirements were bypassed. Many key trial findings either misreported or omitted entirely published reports. By implication, secondary estimates excess morbidity mortality in must be deemed underestimates. Rigorous re-analyses data post-marketing surveillance studies indicate a substantial degree modmRNA-related harms than was initially reported. Confidential Pfizer documents had revealed 1.6 million by August 2022. A third serious injuries cardiovascular, neurological, thrombotic, immunological, reproductive systems, along alarming increase cancers. Moreover, well-designed shown repeated cause immune dysfunction, thereby potentially contributing heightened susceptibility SARS-CoV-2 infections increased risks COVID-19. This paper also discusses insidious influence Bio-Pharmaceutical Complex, closely coordinated collaboration between organizations, pharmaceutical companies, regulatory agencies. We recommend moratorium on until toxicological are conducted.

Language: Английский

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SARS-CoV-2 Spike Protein Mutations and Escape from Antibodies: A Computational Model of Epitope Loss in Variants of Concern

Journal of Chemical Information and Modeling, Journal Year: 2021, Volume and Issue: 61(9), P. 4687 - 4700

Published: Sept. 1, 2021

The SARS-CoV-2 spike (S) protein is exposed on the viral surface and first point of contact between virus host. For these reasons it represents prime target for Covid-19 vaccines. In recent months, variants this have started to emerge. Their ability reduce or evade recognition by S-targeting antibodies poses a threat immunological treatments raises concerns their consequences vaccine efficacy. To develop model able predict potential impact S-protein mutations antibody binding sites, we performed unbiased multi-microsecond molecular dynamics several glycosylated applied straightforward structure-dynamics-energy based strategy changes in immunogenic regions each variant. We recover known epitopes reference D614G sequence. By comparing our results, obtained isolated S-proteins solution, recently published data reactivity new S variants, directly show that modifications consistently translate into loss potentially immunoreactive regions. Our findings can thus be qualitatively reconnected experimentally characterized decreased some Abs elicited against dominant S-sequence recognize variants. While study computational epitope-prediction portable could immunoreactivity mutants proteins interest whose structures been characterized, helping development/selection vaccines control emerging

Language: Английский

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The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour

Computational and Structural Biotechnology Journal, Journal Year: 2021, Volume and Issue: 20, P. 139 - 147

Published: Dec. 11, 2021

The SARS-CoV-2 spike protein is the first contact point between virus and host cells mediates membrane fusion. Recently, a fatty acid binding site was identified in (Toelzer

Language: Английский

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