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Introduction: The significance of automated drug design using virtual generative models has steadily grown in recent years. While deep learning-driven solutions have received growing attention, only a few modern AI-assisted generative chemistry platforms have demonstrated the ability to produce valuable structures. At the same time, virtual fragment-based drug design, which was previously less popular due to the high computational costs, has become more attractive with the development of new chemoinformatic techniques and powerful computing technologies. Methods: We developed Quantum-assisted Fragment-based Automated Structure Generator (QFASG), a fully automated algorithm designed to construct ligands for a target protein using a library of molecular fragments. QFASG was applied to generating new structures of CAMKK2 and ATM inhibitors. Results: New low-micromolar inhibitors of CAMKK2 and ATM were designed using the algorithm. Discussion: These findings highlight the algorithm's potential in designing primary hits for further optimization and showcase the capabilities of QFASG as an effective tool in this field.
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Broadband transient absorption spectroscopy is used to study the photoisomerization of stiffened stilbenes in solution, specifically E/ Z mixtures of bis(benzocyclobutylidene) (t4, c4) and ( E)-1-(2,2-dimethyltetralinylidene)-2-2-dimethyltetraline (t6). Upon excitation to S1, all evolve to perpendicular molecular conformation P, followed by decay to S0, while the spectra and the kinetic behavior crucially depend on the size of the stiffening ring. In 4, contrary to all previously studied stilbenes, the trans and cis absorption and excited-state spectra are nearly indistinguishable, while the corresponding isomerization times are comparable: τi = 166 ps for t4 and τi = 64 ps for c4 in n-hexane, as opposed to 114 and 45 ps in acetonitrile, respectively. Faster isomerization in polar solvents agrees with the zwitterionic character of the P state. In t6, torsion to P is effectively barrier-less and completes within 0.3 ps, the S1 â P evolution being directly traceable through the transient spectra of stimulated emission and that of excited-state absorption. In n-hexane, the P state is remarkably long-lived, τP = 1840 ps, but the lifetime drops down to 35 ps in acetonitrile. The trans-to-cis photoisomerization yield for t6 is measured to be 20%, while for t4, it remains uncertain. We discuss the effects of stiffening and substitution on the formation and lifetime of the intermediate states through which the stilbene molecules evolve on the S1 energy surface.
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We survey the structure and electronic properties of the family of higher trifluoromethylated C70 (CF3 )n molecules with n=14, 16, 18, and 20. Twenty-two available compounds, of which thirteen are newly obtained and characterized, demonstrate the broad diversity of π-system topologies, which enabled us to study the interplay between the CF3 addition pattern and the electronic properties. UV/Vis spectroscopic and cyclic voltammetric studies demonstrate the importance of the exact addition pattern rather than the plain number of addends. Of particular interest is the skew pentagonal pyramid (SPP) addition pattern, which enables formation of closed-shell cyclopentadienyl anions C70 (CF3 )n-1- through CF3 detachment upon electron transfer. A detailed study of the process is presented for a SPP-C70 (CF3 )16 where potentiostatic electrolysis at the second reduction potential gives C70 (CF3 )15- oxidizable to a persistent C70 (CF3 )15. radical. Together with the literature data for the lower C70 (CF3 )n compounds with n=2-12, the present results show good correlation between the experimental boundary level positions and the DFT predictions. The compounds turn out to be electron acceptor molecular semiconductors with experimental LUMO energies and HOMO-LUMO gaps within the ranges of -4.3 to -3.7â eV and 1.6 to 3.3â eV, respectively, depending on the shape of the conjugated fragments. The HOMO levels fall within the range of -5.6 to -6.9â eV and show linear correlation with the number of addends.
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The first example of three alternative chlorination-promoted skeletal transformation pathways in the same fullerene cage is presented. Isolated-pentagon-rule (IPR) C102(19) undergoes both Stone-Wales rotations to give non-IPR #283794C102Cl20 and C2 losses to form nonclassical C98 and non-IPR C96. X-ray structural characterization of the transformation products and a theoretical study of their formation pathways are reported.
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A new case of chlorination-promoted fullerene cage shrinkage is reported. Chlorination of C90 (isolated pentagon rule isomer no. 28) with VCl4 afforded C88Cl22 with a nonclassic carbon cage (NCC) containing 1 heptagon and 13 pentagons including 2 fused pairs flanking the heptagon. The pathway of C2 abstraction from the C90 cage is suggested on the basis of density functional theory calculations.
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A novel case of chlorination-promoted skeletal transformation in higher fullerenes is reported. Chlorination of C(82) [isolated pentagon rule (IPR) isomer no. 3] with SbCl(5) results in two consecutive Stone-Wales rearrangements into non-IPR C(82)Cl(28) with one pair of fused pentagons. An extensive theoretical study of the transformation pathways in C(82) revealed that the thermodynamically favorable rearrangement into non-IPR C(82)Cl(28) needs a comparatively low activation energy.
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Chlorination of the D(2)-C(76) fullerene under various conditions is studied in detail. It is found that, in addition to the previously known C(76)Cl(18) and C(76)Cl(34), a number of intermediate chlorides are formed, with all molecules falling into two structural types. The first type is observed in the C(76)Cl(18)-C(76)Cl(28) range, whereas further chlorination provides the C(76)Cl(30)-C(76)Cl(34) compounds of the second type exhibiting a major change in the addition motif. We also present a detailed theoretical rationalization of the previously observed skeletal rearrangement in the D(2)-C(76) that affords the non-IPR (18917)C(76)Cl(24) compound.
