RESUMEN
Ion channels play a crucial role in a variety of physiological and pathological processes, making them attractive targets for drug development in diseases such as diabetes, epilepsy, hypertension, cancer, and chronic pain. Despite the importance of ion channels in drug discovery, the vastness of chemical space and the complexity of ion channels pose significant challenges for identifying drug candidates. The use of in silico methods in drug discovery has dramatically reduced the time and cost of drug development and has the potential to revolutionize the field of medicine. Recent advances in computer hardware and software have enabled the screening of ultra-large compound libraries. Integration of different methods at various scales and dimensions is becoming an inevitable trend in drug development. In this review, we provide an overview of current state-of-the-art computational chemistry methodologies for ultra-large compound library screening and their application to ion channel drug discovery research. We discuss the advantages and limitations of various in silico techniques, including virtual screening, molecular mechanics/dynamics simulations, and machine learning-based approaches. We also highlight several successful applications of computational chemistry methodologies in ion channel drug discovery and provide insights into future directions and challenges in this field.
RESUMEN
Density functional theory (DFT) and multiconfigurational self-consistent field theory (MCSCF) methods are employed to investigate variation of the electronic properties of various N-heterocyclic carbenes. Alterations to the backbone by increased or decreased conjugation, heteroatom substitution in the NHC ring, and electron-donating or -withdrawing backbone substituents are modeled. The MCSCF calculations show extensive delocalization of both the highest occupied and lowest unoccupied molecular orbitals for NHCs with polymerizable backbone substituents. The free energies of the intermediates and transition structures for benzoin condensation are also shown to be sensitive to substitution of the NHC backbone. Taken together, these results imply great sensitivity of the reactivity of poly(NHC) catalysts to backbone modification at this moiety. Implications with respect to enhancement of poly(NHC)s employed in umpolung catalysis are discussed.
RESUMEN
In our efforts to prepare a diarsenic allotrope supported by two cyclic alkyl amino carbene (CAAC) ligands we stumbled upon the synthesis of the first carbene-supported chloroarsinideneâ 3, which has been fully characterized by a combination of NMR spectroscopic and XRD methods. Although further reduction of 3 was not possible, we found that addition of a second equivalent of CAAC in refluxing toluene afforded the first example of a crystallographically characterized arsamethine cyanine dyeâ (4). The arsenic(I) dye is structurally similar to phosphorus analogues, and contains an arsenide anion with two stereochemically active lone pairs supported by two iminium ligands. The UV/Visible spectrum and redox chemistry of 4 were also explored. Upon reduction with one equivalent of KC8 , 3 is reduced to the originally targeted CAAC2 As2 allotropeâ 6, whereas oxidation provides access to the first example of an arsenic(II) radical dication (5).