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Screening and Simulation Study of Efficacious Antiviral Cannabinoid Compounds as Potential Agents Against SARS-CoV-2
No full textThe proliferation of severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2) and the persistent corona-virus disease 2019 (COVID-19) pandemic emphasize the necessity for novel treatments. Among the diverse pharmacological agents under scrutiny, cannabinoids have garnered attention for their potential antiviral properties. This study utilizes molecular docking and simulation techniques to explore the interaction between cannabinoid drugs and essential SARS-CoV-2 viral proteins to identify potential therapeutic effects. The results suggest favourable binding energies between certain cannabinoid drugs and viral proteins, especially at the active sites of the spike protein. Our computational findings reveal that the ligands Cannabiscitrin and Cannabisin D exhibit the highest binding affinity (approximately -9.11 and –8.84 kcal/mol, respectively) toward the SARS-CoV-2 receptor, while Alacepril displays the lowest affinity (–6.32 kcal/mol) for the SARS-CoV-2 receptor. The findings suggest a potential inhibitory effect of cannabinoid drugs on both viral entry and replication. Furthermore, simulations demonstrate cannabinoid binding to the CB2 receptor, suggesting potential immunomodulatory roles in SARS-CoV-2 infection. This research underscores the promise of cannabinoids as SARS-CoV-2 therapeutic agents, necessitating further validation and clinical exploration
Regio-MPNN: Predicting Regioselectivity for General Metal-Catalyzed Cross-Coupling Reactions using Chemical Knowledge Informed Message Passing Neural Network
No full textAs a fundamental problem in organic chemistry, synthesis planning aims at designing energy and cost-efficient reaction pathways for target compounds. In synthesis planning, it is crucial to understand regioselectivity, or the preference of a reaction over competing reaction sites. Precisely predicting regioselectivity enables early exclusion of unproductive reactions and paves the way to designing high-yielding synthetic routes with minimal separation and material costs. However, it is still at emerging state to combine chemical knowledge and data-driven methods to make practical predictions for regioselectivity. At the same time, metal-catalyzed cross-coupling reactions have profoundly transformed medicinal chemistry, and thus become one of the most frequently encountered types of reactions in synthesis planning. In this work, we for the first time introduce a chemical knowledge informed message passing neural network(MPNN) framework that directly identifies the intrinsic major products for metal-catalyzed cross-coupling reactions with regioselective ambiguity. Integrating both first principle methods and data-driven methods, our model achieves an overall accuracy of 96.51% on the test set of eight typical metal-catalyzed cross-coupling reaction types, including Suzuki-Miyaura, Stille, Sonogashira, Buchwald-Hartwig, Hiyama, Kumada, Negishi, and Heck reactions, outperforming other commonly used model types. To integrate electronic effects with steric effects in regioselectivity prediction, we propose a quantitative method to measure the steric hindrance effect. Our steric hindrance checker can successfully identify regioselectivity induced solely by steric hindrance. Notably under practical scenarios, our model outperforms 6 experimental organic chemists with an average working experience of over 10 years in the organic synthesis industry in terms of predicting major products in regioselective cases. We have also exemplified the practical usage of our model by fixing routes designed by open-access synthesis planning software and improving reactions by identifying low-cost starting materials. To assist general chemists in making prompt decisions about regioselectivity, we have developed a free web-based AI-empowered tool. Our code and web tool have been made available at https://github.com/Chemlex-AI/regioselectivity and https://ai.tools.chemlex.com/region-choose, respectively
Tuning the band gap and structure from wide gap SrBi3O4Cl3 to narrow gap Bi4O4SeCl2 by aliovalent anion substitution
No full textModifying the atomic and electronic structure of materials by chemical substitution is a common method of achieving properties by design. Cations and metal atoms are the most frequent choices for chemical substitution; replacing anions with ones from a different chemical group is unusual due to the very different orbital energies and electronegativities involved. Here we demonstrate full substitution of Se by Cl in the visible band gap material Bi4O4SeCl2 charge balanced y simultaneous replacement of Bi with Sr, all the way to the wide gap photocatalyst material SrBi3O4Cl3. This compositional flexibility is associated with the layer-segregation of Sr and Se atoms. The crystal structure and electronic structure change non-linearly, with a compositional regime of two band gap transitions observed, due to the introduction of in-gap Se states to the electronic structure. The material CaBi3O4Cl3 is also synthesized, revealing the separate effects on the crystal structure of the anion and cation composition. This work presents aliovalent anion substitution in multiple anion materials as a strategy for tuning between narrow and wide gap materials, with properties showing more than one optical transition achievable at intermediate compositions
Phosphorylation Strongly Affects the Inhibition of Human Carbonic Anhydrase I CO2 Hydration Activity
No full textHuman carbonic anhydrases (hCAs) have essential roles in respiration, acid-base balance, and fluid secretion, with implications in diseases such as glaucoma, epilepsy, obesity, and cancer. Of the fifteen known hCAs, human CA I (hCA I) is particularly abundant in erythrocytes, playing a critical role in CO2 transport. Despite extensive research on hCA I, the impact of post-translational modifications (PTMs), particularly phosphorylation, on its catalytic activity and inhibitor binding remains poorly understood. Although multiple phosphorylation sites have been identified in hCA I in vivo through high-throughput proteomics studies including at the highly conserved Ser51 residue, the functional consequences of these modifications are not well characterized. We investigated the effects of a phosphomimic mutation at Ser51 on hCA I, examining its catalytic efficiency and susceptibility to inhibition by sulfonamides and anions. Using a recombinant expression system and a stopped-flow kinetic assay, we characterized the CO2 hydration activity and inhibition profiles of S51E hCA I compared to the wild type enzyme. Our results demonstrate that the S51E mutation increases the catalytic turnover rate (kcat) from 2.0 × 105 s-1 to 2.6 × 105 s-1 but significantly decreases substrate affinity, raising the Michaelis constant (KM) from 4.0 mM to 13.9 mM, reducing overall catalytic efficiency by over 50%. Inhibition studies with a panel of 41 sulfonamides revealed that the S51E mutation dramatically alters inhibitor sensitivity, particularly for the most effective inhibitors. For example, 15 of the 16 most effective sulfonamide inhibitors for hCA I (with KIs <350 nM) were an average of over 35-fold less effective in inhibiting S51E hCA I than the wild type. For example, the KI of the anticonvulsant zonisamide increased from 31 nM for the wild type hCA I to 4 µM. The inhibition profile with a panel of 37 small anions further indicated that the S51E mutant exhibited significantly reduced susceptibility to inhibition by 24 out of 37 tested anions, with some KI values increasing by up to 11,000-fold for inhibitors like hydrogen sulfide. This study underscores the significant impact that phosphorylation may have on hCA I function and inhibition. By characterizing the effects of phosphorylation on the CO2 hydration activity and inhibitor sensitivity of hCA I, these findings represent early steps in developing more selective proteoform-specific inhibitors, which could lead to more effective treatments for diseases involving carbonic anhydrases
Origin of catalysis by [Ga4L6]12- metallocage on the Prins reaction
No full textThe Prins cyclization of citronellal is a significant reaction for synthesizing new carbon–carbon bonds, typically catalyzed by acidic conditions, serving as a crucial industrial intermediate for menthol production. The present work aims to investigate, by means of computational methods, the host-guest catalytic mechanism within the [Ga4L6]12- metallocage, which promotes the formation of minor alkene products, emulating the selectivity observed in biological terpene synthases. A combination of molecular dynamics simulations, DFT, and QM/MM calculations were employed to explore the reaction profiles, revealing the dynamics of encapsulation and the role of protonation and cyclization steps. Our study confirms that the metallocage does not directly modify the reaction, but rather provides a unique microenvironment within its cavity that facilitates acid-catalyzed reactions under basic or neutral conditions in solution. Indeed, modification of basicity of the citronellal reactant once encapsulated turns out to be critical for the process. Moreover, conversely to what is expected, the metallocage does not promote a conformational preorganization of the guest to a more compact conformation prone to undertake the cyclization. Identifying these factors offers a detailed understanding of rate enhancement by metallocages that can be of general applicability
Development of tailless homologue receptor (TLX) agonist chemical tools
No full textThe tailless homologue receptor (TLX) is a ligand-activated transcription factor acting as master regulator of neural stem cell homeostasis. Despite its promising potential in neurodegenerative disease treatment, TLX ligands are rare but required to explore phenotypic effects of TLX modulation and for target validation. We have systematically studied and optimized a TLX agonist scaffold obtained by fragment fusion. Structural modification enabled the development of two TLX agonists endowed with nanomolar potency and binding affinity. Both exhibited favorable chemical tool characteristics including high selectivity and low toxicity. Most notably, the TLX agonists comprise different scaffolds and display high chemical diversity enabling a use as set for target identification and validation studies
Synthesis of Thienoacenes by Electrochemical Double C–S Cyclization Using a Halogen Mediator: Utility of an S-MOM Group for Halogen-Mediated Electrolysis
No full textElectrochemical synthesis of [1]benzothieno[3,2-b][1]benzothiophene (BTBT) derivatives from S-methoxymethyl (MOM)-protected bis(o-sulfanylphenyl)acetylene derivatives is described. In the presence of Bu4NBr as a halogen mediator, electrochemical double C–S cyclization proceeded smoothly. MOM protection of thiols was essential for the reaction. While S-Me or S-p-methoxybenzyl (PMB)-protected bis(o-sulfanylphenyl)acetylenes did not afford BTBT and bromocyclized products were predominantly obtained, BTBT was selectively obtained when a similar compound protected with an S-MOM group was used in the reaction. Addition of H2O was significant for the reaction as both a sacrificial agent and a trapping agent for the eliminated MOM group. A variety of symmetrical and asymmetrical BTBT derivatives were obtained under the optimal conditions. Control experiments and DFT calculations suggest that the double-cyclization did not proceed concertedly, but rather in a stepwise fashion. The S-MOM protection strategy is also effective for the electrochemical synthesis of a more π-expanded thienoacene such as dibenzo[d,d’]thieno[3,2-b;4,5-b’]dithiophene (DBTDT)
Structure elucidation of the daptomycin products generated upon heterologous expression of the daptomycin resistance gene cluster drcAB
No full textRecently, a high-level daptomycin (DAP) resistant Mammaliicoccus sciuri strain (TS92) was identified which mediates a 33 percent decline of DAP when incubated in Mueller-Hinton (MH) medium. The genetic background of the DAP resistance in TS92 is a newly discovered two-gene operon, named drcAB, whose expression was reported to impair the structural integrity of DAP, eventually leading to its inactivation. Here we set out to elucidate the chemical nature of drcAB-mediated DAP modification by applying a general unknown comparative screening (GUCS) approach in high-resolution mass spectrometry. DAP in MH medium was incubated with Staphylococcus aureus strain RN4220_Pxyl/tet-drcAB, which carries the drcAB operon under control of an inducible promotor on a plasmid, and GUCS test and reference samples were obtained upon and without drcAB expression. A two-step process catalyzed by DrcAB was discovered, comprising a structural alteration of DAP. The mass spectrometric data indicate an N-substitution at the aniline moiety of kynurenine with dehydroalanine, and subsequently, a cleavage of the ester bond of the DAP core between kynurenine and threonine by means of water. The structures postulated were confirmed by comparison of in silico versus measured fragmentation patterns
Extensive Biotransformation Profiling of AZD8205, an Anti-B7-H4 Antibody-Drug Conjugate, Elucidates Pathways Underlying its Stability In Vivo
No full textWhat happens to macromolecules in vivo? What drives structure-activity relationship and in vivo stability for antibody-drug conjugates (ADCs)? These interrelated questions are increasingly relevant due to the re-emerging importance of ADCs as an impactful therapeutic modality and the gaps that exist in our understanding of ADC structural determinants that underlie ADC in vivo stability. Complex macromolecules, such as ADCs may undergo changes in vivo due to their intricate structure as biotransformations may occur on the linker, the payload and/or at the modified conjugation site. Furthermore, dissection of ADC metabolism presents a substantial analytical challenge due to the difficulty in identification or quantification of minor changes on a large macromolecule. We employed immunocapture-LCMS methods to evaluate in vivo changes in drug-antibody ratio (DAR) profile in four different lead ADCs. This comprehensive characterization revealed that a critical structural determinant contributing to ADC design was the selection of the linker as the competition between the retro-Michael deconjugation and thio-succinimide hydrolysis reactions resulted in superb conjugation stability in vivo. These data, in conjunction with additional factors, informed the selection of AZD8205, a B7-H4-directed cysteine-conjugated ADC bearing a novel topoisomerase I inhibitor payload, with durable DAR, currently being studied in the clinic for the potential treatment of solid malignancies (NCT05123482). These results highlight the relevance of studying macromolecule biotransformation and elucidating the ADC structure-in vivo stability relationship. The comprehensive nature of this work increases confidence in our understanding of these processes. We hope this analytical approach can inform future development of bioconjugate drug candidates.
A Broadly Applicable Strategy to Aminate Azines Enabled by Electronically Tuned Phosphine Reagents.
No full textWe describe a strategy for aminating pyridines and other azines via phosphonium salt intermediates. Precisely tuning the electronic properties of the phosphonium ion was key for C–N bond formation via an SNAr-halogenation, SNAr-amination sequence. The process accommodates a wide range of amine classes and pyridine coupling partners and is viable for applications such as late-stage amination of complex pharmaceuticals and fragment-fragment coupling reactions. The capacity to rapidly modify the structure of the phosphine reagent was decisive and is a valuable feature in pseudohalide design