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Article ; Online: Systematic modification of functionality in disordered elastic networks through free energy surface tailoring.

Mendels, Dan / Byléhn, Fabian / Sirk, Timothy W / de Pablo, Juan J

2023 Volume 9, Issue 23, Page(s) eadf7541

Abstract: A combined machine learning-physics-based approach is explored for molecular and materials engineering. Specifically, collective variables, akin to those used in enhanced sampled simulations, are constructed using a machine learning model trained on data ...

Abstract	A combined machine learning-physics-based approach is explored for molecular and materials engineering. Specifically, collective variables, akin to those used in enhanced sampled simulations, are constructed using a machine learning model trained on data gathered from a single system. Through the constructed collective variables, it becomes possible to identify critical molecular interactions in the considered system, the modulation of which enables a systematic tailoring of the system's free energy landscape. To explore the efficacy of the proposed approach, we use it to engineer allosteric regulation and uniaxial strain fluctuations in a complex disordered elastic network. Its successful application in these two cases provides insights regarding how functionality is governed in systems characterized by extensive connectivity and points to its potential for design of complex molecular systems.
Language	English
Publishing date	2023-06-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adf7541
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Molecular analysis of the type III interferon complex and its applications in protein engineering.

Grubbe, William S / Byléhn, Fabian / Alvarado, Walter / de Pablo, Juan J / Mendoza, Juan L

Biophysical journal

2023 Volume 122, Issue 21, Page(s) 4254–4263

Abstract: Type III interferons (IFNλs) are cytokines with critical roles in the immune system and are attractive therapeutic candidates due to their tissue-specific activity. Despite entering several clinical trials, results have demonstrated limited efficacy and ... ...

Abstract	Type III interferons (IFNλs) are cytokines with critical roles in the immune system and are attractive therapeutic candidates due to their tissue-specific activity. Despite entering several clinical trials, results have demonstrated limited efficacy and potency, partially attributed to low-affinity protein-protein interactions (PPIs) responsible for receptor complex formation. Subsequently, structural studies of the native IFNλ signaling complexes remain inaccessible. While protein engineering can overcome affinity limitations, tools to investigate low-affinity systems like these remain limited. To provide insights into previous efforts to strengthen the PPIs within this complex, we perform a molecular analysis of the extracellular ternary complexes of IFNλ3 using both computational and experimental approaches. We first use molecular simulations and modeling to quantify differences in PPIs and residue strain fluctuations, generate detailed free energy landscapes, and reveal structural differences between an engineered, high-affinity complex, and a model of the wild-type, low-affinity complex. This analysis illuminates distinct behaviors of these ligands, yielding mechanistic insights into IFNλ complex formation. We then apply these computational techniques in protein engineering and design by utilizing simulation data to identify hotspots of interaction to rationally engineer the native cytokine-receptor complex for increased stability. These simulations are then validated by experimental techniques, showing that a single mutation at a computationally predicted site of interaction between the two receptors increases PPIs and improves complex formation for all IFNλs. This study highlights the power of molecular dynamics simulations for protein engineering and design as applied to the IFNλ family but also presents a potential tool for analysis and engineering of other systems with low-affinity PPIs.
MeSH term(s)	Interferon Lambda ; Protein Binding ; Protein Engineering/methods ; Molecular Dynamics Simulation ; Signal Transduction
Chemical Substances	Interferon Lambda
Language	English
Publishing date	2023-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2023.09.021
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors.

Perez-Lemus, Gustavo R / Menéndez, Cintia A / Alvarado, Walter / Byléhn, Fabian / de Pablo, Juan J

Science advances

2022 Volume 8, Issue 1, Page(s) eabj4526

Abstract: To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on ... ...

Abstract	To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs.
Language	English
Publishing date	2022-01-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abj4526
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Book ; Online: Systematic Modification of Functionality in Disordered Elastic Networks Through Free Energy Surface Tailoring

Mendels, Dan / Byléhn, Fabian / Sirk, Timothy W. / de Pablo, Juan J.

2022

Abstract: Advances in manufacturing and characterization of complex molecular systems have created a need for new methods for design at molecular length scales. Emerging approaches are increasingly relying on the use of Artificial Intelligence (AI), and the ... ...

Abstract	Advances in manufacturing and characterization of complex molecular systems have created a need for new methods for design at molecular length scales. Emerging approaches are increasingly relying on the use of Artificial Intelligence (AI), and the training of AI models on large data libraries. This paradigm shift has led to successful applications, but shortcomings related to interpretability and generalizability continue to pose challenges. Here, we explore an alternative paradigm in which AI is combined with physics-based considerations for molecular and materials engineering. Specifically, collective variables, akin to those used in enhanced sampled simulations, are constructed using a machine learning (ML) model trained on data gathered from a single system. Through the ML-constructed collective variables, it becomes possible to identify critical molecular interactions in the system of interest, the modulation of which enables a systematic tailoring of the system's free energy landscape. To explore the efficacy of the proposed approach, we use it to engineer allosteric regulation, and uniaxial strain fluctuations in a complex disordered elastic network. Its successful application in these two cases provides insights regarding how functionality is governed in systems characterized by extensive connectivity, and points to its potential for design of complex molecular systems.
Keywords	Condensed Matter - Soft Condensed Matter ; Condensed Matter - Materials Science ; Physics - Biological Physics ; Physics - Chemical Physics ; Physics - Computational Physics
Subject code	006
Publishing date	2022-07-08
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Modeling the Binding Mechanism of Remdesivir, Favilavir, and Ribavirin to SARS-CoV-2 RNA-Dependent RNA Polymerase.

Byléhn, Fabian / Menéndez, Cintia A / Perez-Lemus, Gustavo R / Alvarado, Walter / de Pablo, Juan J

ACS central science

2021 Volume 7, Issue 1, Page(s) 164–174

Abstract: Recent efforts to repurpose drugs to combat COVID-19 have identified Remdesivir as a candidate. It acts on the RNA-dependent, RNA polymerase (RdRp) of the SARS-CoV-2 virus, a protein complex responsible for mediating replication of the virus's genome. ... ...

Abstract	Recent efforts to repurpose drugs to combat COVID-19 have identified Remdesivir as a candidate. It acts on the RNA-dependent, RNA polymerase (RdRp) of the SARS-CoV-2 virus, a protein complex responsible for mediating replication of the virus's genome. However, its exact action mechanism, and that of other nucleotide analogue inhibitors, is not known. In this study, we examine at the molecular level the interaction of this drug and that of similar nucleotide analogue inhibitors, ribavirin and favilavir, by relying on atomistic molecular simulations and advanced sampling. By analyzing the binding free energies of these different drugs, it is found that all of them bind strongly at the active site. Surprisingly, however, ribavirin and favilavir do not bind the nucleotide on the complementary strand as effectively and seem to act by a different mechanism than remdesivir. Remdesivir exhibits similar binding interactions to the natural base adenine. Moreover, by analyzing remdesivir at downstream positions of the RNA, we also find that, consistent with a "delayed" termination mechanism, additional nucleotides can be incorporated after remdesivir is added, and its highly polar 1'-cyano group induces a set of conformational changes that can affect the normal RdRp complex function. By analyzing the fluctuations of residues that are altered by remdesivir binding, and comparing them to those induced by lethal point mutations, we find a possible secondary mechanism in which remdesivir destabilizes the protein complex and its interactions with the RNA strands.
Language	English
Publishing date	2021-01-06
Publishing country	United States
Document type	Journal Article
ISSN	2374-7943
ISSN	2374-7943
DOI	10.1021/acscentsci.0c01242
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Article ; Online: Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease.

Menéndez, Cintia A / Byléhn, Fabian / Perez-Lemus, Gustavo R / Alvarado, Walter / de Pablo, Juan J

Science advances

2020 Volume 6, Issue 37

Abstract: There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus' ... ...

Abstract	There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus' main protease, M
MeSH term(s)	Antiviral Agents/metabolism ; Antiviral Agents/pharmacology ; Azoles/metabolism ; Azoles/pharmacology ; Betacoronavirus/drug effects ; Betacoronavirus/metabolism ; Binding Sites ; COVID-19 ; Catalytic Domain/drug effects ; Coronavirus 3C Proteases ; Coronavirus Infections/drug therapy ; Cysteine Endopeptidases/metabolism ; Drug Repositioning ; Humans ; Models, Molecular ; Molecular Dynamics Simulation ; Organoselenium Compounds/metabolism ; Organoselenium Compounds/pharmacology ; Pandemics ; Pneumonia, Viral/drug therapy ; Protein Conformation/drug effects ; SARS-CoV-2 ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; Azoles ; Organoselenium Compounds ; Viral Nonstructural Proteins ; ebselen (40X2P7DPGH) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Keywords	covid19
Language	English
Publishing date	2020-09-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abd0345
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Article ; Online: Development of Masitinib Derivatives with Enhanced M

Menendez, Cintia A / Mohamed, Adil / Perez-Lemus, Gustavo R / Weiss, Adam M / Rawe, Benjamin W / Liu, Guancen / Crolais, Alex E / Kenna, Emma / Byléhn, Fabian / Alvarado, Walter / Mendels, Dan / Rowan, Stuart J / Tay, Savaş / de Pablo, Juan J

Molecules (Basel, Switzerland)

2023 Volume 28, Issue 18

Abstract: Recently, a high-throughput screen of 1900 clinically used drugs identified masitinib, an orally bioavailable tyrosine kinase inhibitor, as a potential treatment for COVID-19. Masitinib acts as a broad-spectrum inhibitor for human coronaviruses, ... ...

Abstract	Recently, a high-throughput screen of 1900 clinically used drugs identified masitinib, an orally bioavailable tyrosine kinase inhibitor, as a potential treatment for COVID-19. Masitinib acts as a broad-spectrum inhibitor for human coronaviruses, including SARS-CoV-2 and several of its variants. In this work, we rely on atomistic molecular dynamics simulations with advanced sampling methods to develop a deeper understanding of masitinib's mechanism of M
MeSH term(s)	Humans ; Ligands ; Piperidines ; Benzamides ; Thiazoles/pharmacology ; Antiviral Agents/pharmacology ; Protease Inhibitors ; Pyridines
Chemical Substances	masitinib (M59NC4E26P) ; Ligands ; Piperidines ; Benzamides ; Thiazoles ; Antiviral Agents ; Protease Inhibitors ; Pyridines
Language	English
Publishing date	2023-09-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules28186643
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Article: Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease

Menéndez, Cintia A / Byléhn, Fabian / Perez-Lemus, Gustavo R / Alvarado, Walter / de Pablo, Juan J

Sci. Adv

Abstract	There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus' main protease, Mpro, which is involved in gene expression and replication. Among these, ebselen (2-phenyl-1,2-benzoselenazol-3-one) appears to be particularly promising. Here, we examine, at a molecular level, the potential of ebselen to decrease Mpro activity. We find that it exhibits a distinct affinity for the catalytic region. Our results reveal a higher-affinity, previously unknown binding site localized between the II and III domains of the protein. A detailed strain analysis indicates that, on such a site, ebselen exerts a pronounced allosteric effect that regulates catalytic site access through surface-loop interactions, thereby inducing a reconfiguration of water hotspots. Together, these findings highlight the promise of ebselen as a repurposed drug against SARS-CoV-2.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #760208
Database	COVID19

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Article ; Online: Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease

Menéndez, Cintia A. / Byléhn, Fabian / Perez-Lemus, Gustavo R. / Alvarado, Walter / de Pablo, Juan J.

Science Advances

2020 Volume 6, Issue 37, Page(s) eabd0345

Abstract	There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus’ main protease, M pro , which is involved in gene expression and replication. Among these, ebselen (2-phenyl-1,2-benzoselenazol-3-one) appears to be particularly promising. Here, we examine, at a molecular level, the potential of ebselen to decrease M pro activity. We find that it exhibits a distinct affinity for the catalytic region. Our results reveal a higher-affinity, previously unknown binding site localized between the II and III domains of the protein. A detailed strain analysis indicates that, on such a site, ebselen exerts a pronounced allosteric effect that regulates catalytic site access through surface-loop interactions, thereby inducing a reconfiguration of water hotspots. Together, these findings highlight the promise of ebselen as a repurposed drug against SARS-CoV-2.
Keywords	covid19
Language	English
Publisher	American Association for the Advancement of Science (AAAS)
Publishing country	us
Document type	Article ; Online
ZDB-ID	2810933-8
ISSN	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abd0345
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Article ; Online: Development of Masitinib Derivatives with Enhanced M pro Ligand Efficiency and Reduced Cytotoxicity

Cintia A. Menendez / Adil Mohamed / Gustavo R. Perez-Lemus / Adam M. Weiss / Benjamin W. Rawe / Guancen Liu / Alex E. Crolais / Emma Kenna / Fabian Byléhn / Walter Alvarado / Dan Mendels / Stuart J. Rowan / Savaş Tay / Juan J. de Pablo

Molecules, Vol 28, Iss 6643, p

2023 Volume 6643

Abstract	Recently, a high-throughput screen of 1900 clinically used drugs identified masitinib, an orally bioavailable tyrosine kinase inhibitor, as a potential treatment for COVID-19. Masitinib acts as a broad-spectrum inhibitor for human coronaviruses, including SARS-CoV-2 and several of its variants. In this work, we rely on atomistic molecular dynamics simulations with advanced sampling methods to develop a deeper understanding of masitinib’s mechanism of M pro inhibition. To improve the inhibitory efficiency and to increase the ligand selectivity for the viral target, we determined the minimal portion of the molecule (fragment) that is responsible for most of the interactions that arise within the masitinib-M pro complex. We found that masitinib forms highly stable and specific H-bond interactions with M pro through its pyridine and aminothiazole rings. Importantly, the interaction with His 163 is a key anchoring point of the inhibitor, and its perturbation leads to ligand unbinding within nanoseconds. Based on these observations, a small library of rationally designed masitinib derivatives ( M1 – M5 ) was proposed. Our results show increased inhibitory efficiency and highly reduced cytotoxicity for the M3 and M4 derivatives compared to masitinib.
Keywords	masitinib derivatives ; M pro inhibitors ; SARS-CoV-2 ; Organic chemistry ; QD241-441
Subject code	333
Language	English
Publishing date	2023-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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