Abstract
To date, more than 263 million people have been infected with SARS-CoV-2 during the COVID-19 pandemic. In many countries, the global spread occurred in multiple pandemic waves characterized ...by the emergence of new SARS-CoV-2 variants. Here we report a sequence and structural-bioinformatics analysis to estimate the effects of amino acid substitutions on the affinity of the SARS-CoV-2 spike receptor binding domain (RBD) to the human receptor hACE2. This is done through qualitative electrostatics and hydrophobicity analysis as well as molecular dynamics simulations used to develop a high-precision empirical scoring function (ESF) closely related to the linear interaction energy method and calibrated on a large set of experimental binding energies. For the latest variant of concern (VOC), B.1.1.529 Omicron, our Halo difference point cloud studies reveal the largest impact on the RBD binding interface compared to all other VOC. Moreover, according to our ESF model, Omicron achieves a much higher ACE2 binding affinity than the wild type and, in particular, the highest among all VOCs except Alpha and thus requires special attention and monitoring.
Advancing climate change increases the risk of future infectious disease outbreaks, particularly of zoonotic diseases, by affecting the abundance and spread of viral vectors. Concerningly, there are ...currently no approved drugs for some relevant diseases, such as the arboviral diseases chikungunya, dengue or zika. The development of novel inhibitors takes 10–15 years to reach the market and faces critical challenges in preclinical and clinical trials, with approximately 30% of trials failing due to side effects. As an early response to emerging infectious diseases, CavitOmiX allows for a rapid computational screening of databases containing 3D point-clouds representing binding sites of approved drugs to identify candidates for off-label use. This process, known as drug repurposing, reduces the time and cost of regulatory approval. Here, we present potential approved drug candidates for off-label use, targeting the ADP-ribose binding site of Alphavirus chikungunya non-structural protein 3. Additionally, we demonstrate a novel in silico drug design approach, considering potential side effects at the earliest stages of drug development. We use a genetic algorithm to iteratively refine potential inhibitors for (i) reduced off-target activity and (ii) improved binding to different viral variants or across related viral species, to provide broad-spectrum and safe antivirals for the future.
Treatment of COVID-19 with a soluble version of ACE2 that binds to SARS-CoV-2 virions before they enter host cells is a promising approach, however it needs to be optimized and adapted to emerging ...viral variants. The computational workflow presented here consists of molecular dynamics simulations for spike RBD-hACE2 binding affinity assessments of multiple spike RBD/hACE2 variants and a novel convolutional neural network architecture working on pairs of voxelized force-fields for efficient search-space reduction. We identified hACE2-Fc K31W and multi-mutation variants as high-affinity candidates, which we validated in vitro with virus neutralization assays. We evaluated binding affinities of these ACE2 variants with the RBDs of Omicron BA.3, Omicron BA.4/BA.5, and Omicron BA.2.75 in silico. In addition, candidates produced in Nicotiana benthamiana, an expression organism for potential large-scale production, showed a 4.6-fold reduction in half-maximal inhibitory concentration (IC
) compared with the same variant produced in CHO cells and an almost six-fold IC
reduction compared with wild-type hACE2-Fc.
Human proteins are crucial players in both health and disease. Understanding their molecular landscape is a central topic in biological research. Here, we present an extensive dataset of predicted ...protein structures for 42,042 distinct human proteins, including splicing variants, derived from the UniProt reference proteome UP000005640. To ensure high quality and comparability, the dataset was generated by combining state-of-the-art modeling-tools AlphaFold 2, OpenFold, and ESMFold, provided within NVIDIA’s BioNeMo platform, as well as homology modeling using Innophore’s CavitomiX platform. Our dataset is offered in both unedited and edited formats for diverse research requirements. The unedited version contains structures as generated by the different prediction methods, whereas the edited version contains refinements, including a dataset of structures without low prediction-confidence regions and structures in complex with predicted ligands based on homologs in the PDB. We are confident that this dataset represents the most comprehensive collection of human protein structures available today, facilitating diverse applications such as structure-based drug design and the prediction of protein function and interactions.
We discuss charmed mesons in the covariant Dyson-Schwinger-Bethe-Salpeter-equation approach. In particular we computed masses, leptonic decay constants, and an orbital-angular-momentum decomposition ...for a basic set of states. We also report an efficient way to treat the two coupled quark propagator dressing functions via a single function.
The 2022 outbreak of the monkeypox virus already involves, by April 2023, 110 countries with 86,956 confirmed cases and 119 deaths. Understanding an emerging disease on a molecular level is essential ...to study infection processes and eventually guide drug discovery at an early stage. To support this, we provide the so far most comprehensive structural proteome of the monkeypox virus, which includes 210 structural models, each computed with three state-of-the-art structure prediction methods. Instead of building on a single-genome sequence, we generated our models from a consensus of 3,713 high-quality genome sequences sampled from patients within 1 year of the outbreak. Therefore, we present an average structural proteome of the currently isolated viruses, including mutational analyses with a special focus on drug-binding sites. Continuing dynamic mutation monitoring within the structural proteome presented here is essential to timely predict possible physiological changes in the evolving virus.
The current coronavirus pandemic is being combated worldwide by nontherapeutic measures and massive vaccination programs. Nevertheless, therapeutic options such as severe acute respiratory syndrome ...coronavirus 2 (SARS-CoV-2) main-protease (M
) inhibitors are essential due to the ongoing evolution toward escape from natural or induced immunity. While antiviral strategies are vulnerable to the effects of viral mutation, the relatively conserved M
makes an attractive drug target: Nirmatrelvir, an antiviral targeting its active site, has been authorized for conditional or emergency use in several countries since December 2021, and a number of other inhibitors are under clinical evaluation. We analyzed recent SARS-CoV-2 genomic data, since early detection of potential resistances supports a timely counteraction in drug development and deployment, and discovered accelerated mutational dynamics of M
since early December 2021.
We performed a comparative analysis of 10.5 million SARS-CoV-2 genome sequences available by June 2022 at GISAID to the NCBI reference genome sequence NC_045512.2. Amino-acid exchanges within high-quality regions in 69,878 unique M
sequences were identified and time- and in-depth sequence analyses including a structural representation of mutational dynamics were performed using in-house software.
The analysis showed a significant recent event of mutational dynamics in M
. We report a remarkable increase in mutational variability in an eight-residue long consecutive region (R188-G195) near the active site since December 2021.
The increased mutational variability in close proximity to an antiviral-drug binding site as described herein may suggest the onset of the development of antiviral resistance. This emerging diversity urgently needs to be further monitored and considered in ongoing drug development and lead optimization.
Exploiting an interplay of the Bethe-Salpeter equation enabling us to regard mesons as bound states of quark and antiquark and the Dyson-Schwinger equation controlling the dressed quark propagator, ...we amend existing studies of quarkonia by a comprehensive description of open-flavour mesons composed of all conceivable combinations of quark flavour. Employing throughout a fixed set of model parameters, we predict some basic characteristics of these mesons,
i.e.,
their masses, leptonic decay constants and corresponding in-hadron condensates entering in a generalized formulation of the Gell-Mann-Oakes-Renner relation.
Emerging computational tools promise to revolutionize protein engineering for biocatalytic applications and accelerate the development timelines previously needed to optimize an enzyme to its more ...efficient variant. For over a decade, the benefits of predictive algorithms have helped scientists and engineers navigate the complexity of functional protein sequence space. More recently, spurred by dramatic advances in underlying computational tools, the promise of faster, cheaper, and more accurate enzyme identification, characterization, and engineering has catapulted terms such as artificial intelligence and machine learning to the must-have vocabulary in the field. This Perspective aims to showcase the current status of applications in pharmaceutical industry and also to discuss and celebrate the innovative approaches in protein science by highlighting their potential in selected recent developments and offering thoughts on future opportunities for biocatalysis. It also critically assesses the technology’s limitations, unanswered questions, and unmet challenges.
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