Podophyllotoxin is probably the most prominent representative of lignan natural products. Deoxy‐, epi‐, and podophyllotoxin, which are all precursors to frequently used chemotherapeutic agents, were ...prepared by a stereodivergent biotransformation and a biocatalytic kinetic resolution of the corresponding dibenzylbutyrolactones with the same 2‐oxoglutarate‐dependent dioxygenase. The reaction can be conducted on 2 g scale, and the enzyme allows tailoring of the initial, “natural” structure and thus transforms various non‐natural derivatives. Depending on the substitution pattern, the enzyme performs an oxidative C−C bond formation by C−H activation or hydroxylation at the benzylic position prone to ring closure.
Taming iron: Podophyllotoxin and congeners were prepared by chemoenzymatic total synthesis employing the 2‐oxoglutarate‐dependent iron enzyme from Podophyllum hexandrum. The reaction outcome was changed from an enantiodivergent to a kinetic resolution process by substrate engineering. Modifications of the substrate allowed the kinetic resolution of dibenzylbutyrolactones.
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.
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.
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.
The COVID‐19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small‐molecule ...drugs that are widely available, including in low‐ and middle‐income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the “Billion molecules against COVID‐19 challenge”, to identify small‐molecule inhibitors against SARS‐CoV‐2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find ‘consensus compounds’. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding‐, cleavage‐, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS‐CoV‐2 treatments.
Abstract
Podophyllotoxin (
1
) ist einer der bekanntesten Vertreter von natürlich vorkommenden Lignanen. Deoxy‐,
epi
‐ und Podophyllotoxin, welche alle Vorstufen für häufig verwendete ...chemotherapeutische Verbindungen darstellen, wurden mithilfe einer stereodivergenten Biotransformation und biokatalytischen kinetischen Racematspaltung der jeweiligen Dibenzylbutyrolactone durch dieselbe 2‐Oxoglutarat‐abhängige Dioxygenase (2‐ODD) hergestellt. Zudem konnte gezeigt werden, dass ein “Upscaling” der Reaktion auf 2 g möglich ist, sowie dass das 2‐ODD‐Enzym Modifikationen des “natürlichen” Substrates toleriert und somit verschiedenste nichtnatürliche Derivate umsetzen kann. Das Enzym führt je nach Substituentenmuster entweder eine oxidative C‐C‐Bindungsbildung durch C‐H‐Aktivierung oder Hydroxylierung an der für die Ringschließung zugänglichen benzylischen Position durch.
Podophyllotoxin (1) ist einer der bekanntesten Vertreter von natürlich vorkommenden Lignanen. Deoxy‐, epi‐ und Podophyllotoxin, welche alle Vorstufen für häufig verwendete chemotherapeutische ...Verbindungen darstellen, wurden mithilfe einer stereodivergenten Biotransformation und biokatalytischen kinetischen Racematspaltung der jeweiligen Dibenzylbutyrolactone durch dieselbe 2‐Oxoglutarat‐abhängige Dioxygenase (2‐ODD) hergestellt. Zudem konnte gezeigt werden, dass ein “Upscaling” der Reaktion auf 2 g möglich ist, sowie dass das 2‐ODD‐Enzym Modifikationen des “natürlichen” Substrates toleriert und somit verschiedenste nichtnatürliche Derivate umsetzen kann. Das Enzym führt je nach Substituentenmuster entweder eine oxidative C‐C‐Bindungsbildung durch C‐H‐Aktivierung oder Hydroxylierung an der für die Ringschließung zugänglichen benzylischen Position durch.
Gebändigtes Eisen: Podophyllotoxin und Derivate wurden durch chemoenzymatische Totalsynthese unter Verwendung der Eisen‐abhängigen Dioxygenase aus Podophyllum hexandrum hergestellt. Mittels Substrat‐Engineering konnte der biologische Schritt von einem enantiodivergenten zu einem racematspaltenden Schlüsselschritt umgelenkt werden. Derivate des natürlichen Substrats ermöglichen die Racematspaltung von Dibenzylbutyrolaktonen.
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