Development of a Multi-Target Pharmacophore-Based Virtual Screening Agent Against COVID-19 DOI Creative Commons

Nashwa A. Ibrahim,

Ahmed M. Gouda, Hany A.M. El-Sherief

и другие.

Al-Mustaqbal Journal of Pharmaceutical and Medical Sciences, Год журнала: 2024, Номер 2(1)

Опубликована: Май 30, 2024

The worldwide outbreak of the COVID-19 pandemic compelled scientists to develop new, highly effective therapeutic approaches fight it. Multitarget drugs have been proven be in managing complex disorders. But designing multitarget is a great challenge. In this study, prevent lack efficacy due viral mutation escape, multi-target agent against virus was discovered. As crucial targets, RNA-dependent RNA polymerase (RdRp), main protease (Mpro), and SARS-CoV-2 Nsp15 were selected. A pharmacophore model developed using native ligands chosen targets. This used screen ZINC Drug Database for commercially available compounds having similar features experimentally tested drugs. Pharmacophore-based virtual screening yielded 1331 hits, which further docked into binding sites selected proteins PyRx AutoDock Vina. Evaluation docking results revealed that glisoxepide (Zn 00537804) has highest scores three target proteins. It showed free energies -6.8, -6.2, -7.8 kcal/mol towards Mpro, Nsp15, RdRp, respectively. According an silico ADME follows Lipinski's rule. molecular dynamics simulation study subsequent investigations had good stability within active promise as potential treatment still needs evaluated through experimental research.

Язык: Английский

Phenotypic evolution of SARS-CoV-2 spike during the COVID-19 pandemic DOI Creative Commons
Wilhelm Furnon, Vanessa M. Cowton, Giuditta De Lorenzo

и другие.

Nature Microbiology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Abstract SARS-CoV-2 variants are mainly defined by mutations in their spike. It is therefore critical to understand how the evolutionary trajectories of spike affect virus phenotypes. So far, it has been challenging comprehensively compare many spikes that emerged during pandemic a single experimental platform. Here we generated panel recombinant viruses carrying different proteins from 27 circulating between 2020 and 2024 same genomic background. We then assessed several phenotypic traits both vitro vivo. found distinct among before after emergence Omicron variants. Spike post-Omicron maintained enhanced tropism for nasal epithelium large airways but displayed, over time, typical pre-Omicron Hence, with features pre- may continue emerge future.

Язык: Английский

Процитировано

2
Antibodies utilizing VL6-57 light chains target a convergent cryptic epitope on SARS-CoV-2 spike protein and potentially drive the genesis of Omicron variants DOI Creative Commons
Qihong Yan, Xijie Gao, Banghui Liu

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 31, 2024

Abstract Continued evolution of SARS-CoV-2 generates variants to challenge antibody immunity established by infection and vaccination. A connection between population genesis virus has long been suggested but its molecular basis remains poorly understood. Here, we identify a class neutralizing public antibodies defined their shared usage VL6-57 light chains. Although heavy chains diverse genotypes are utilized, convergent HCDR3 rearrangements have observed among these cooperate with germline LCDRs target epitope RBD residues S371-S373-S375. Antibody repertoire analysis identifies that this is present in SARS-CoV-2-naive individuals clonally expanded most COVID-19 patients. We confirm Omicron-specific substitutions at S371, S373 S375 mediate escape the class. These findings support constitutes potential immune pressure promoting introduction S371L/F-S373P-S375F Omicron variants. The results provide further evidence antigenic driven mediated immunity.

Язык: Английский

Процитировано

4
The Compensatory Effect of S375F on S371F Is Vital for Maintaining the Infectivity of SARS‐CoV‐2 Omicron Variants DOI Creative Commons
Shuo Liu, Pan Liu,

Qiong Lu

и другие.

Journal of Medical Virology, Год журнала: 2025, Номер 97(3)

Опубликована: Март 1, 2025

The emergence of Omicron variants dramatically changed the transmission rate and infection characteristics compared to previously prevalent strains, primarily due spike protein mutations. However, impact individual mutations remained unclear. Here, we used virus-like particle (VLP) pseudotyped investigate functional contributions by 12 common in protein. We found that S371F mutation receptor binding domain (RBD) led a 5- 10-fold decrease ACE2 utilization efficiency viral infectivity, respectively, accompanied 11-fold reduction neutralization sensitivity monoclonal antibodies. S375F RBD had compensatory effect, rescuing infectivity variant. Based on molecular dynamics simulations, proposed "tug war" model explain this compensation phenomenon. These results provide comprehensive dynamic perspective evolution important pandemic virus.

Язык: Английский

Процитировано

0
Development of a Multi-Target Pharmacophore-Based Virtual Screening Agent Against COVID-19 DOI Creative Commons

Nashwa A. Ibrahim,

Ahmed M. Gouda, Hany A.M. El-Sherief

и другие.

Al-Mustaqbal Journal of Pharmaceutical and Medical Sciences, Год журнала: 2024, Номер 2(1)

Опубликована: Май 30, 2024

The worldwide outbreak of the COVID-19 pandemic compelled scientists to develop new, highly effective therapeutic approaches fight it. Multitarget drugs have been proven be in managing complex disorders. But designing multitarget is a great challenge. In this study, prevent lack efficacy due viral mutation escape, multi-target agent against virus was discovered. As crucial targets, RNA-dependent RNA polymerase (RdRp), main protease (Mpro), and SARS-CoV-2 Nsp15 were selected. A pharmacophore model developed using native ligands chosen targets. This used screen ZINC Drug Database for commercially available compounds having similar features experimentally tested drugs. Pharmacophore-based virtual screening yielded 1331 hits, which further docked into binding sites selected proteins PyRx AutoDock Vina. Evaluation docking results revealed that glisoxepide (Zn 00537804) has highest scores three target proteins. It showed free energies -6.8, -6.2, -7.8 kcal/mol towards Mpro, Nsp15, RdRp, respectively. According an silico ADME follows Lipinski's rule. molecular dynamics simulation study subsequent investigations had good stability within active promise as potential treatment still needs evaluated through experimental research.

Язык: Английский

Процитировано

0