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Nature Reviews. Drug Discovery Sep 2023The development of bioactive small molecules as probes or drug candidates requires discovery platforms that enable access to chemical diversity and can quickly reveal... (Review)
Review
The development of bioactive small molecules as probes or drug candidates requires discovery platforms that enable access to chemical diversity and can quickly reveal new ligands for a target of interest. Within the past 15 years, DNA-encoded library (DEL) technology has matured into a widely used platform for small-molecule discovery, yielding a wide variety of bioactive ligands for many therapeutically relevant targets. DELs offer many advantages compared with traditional screening methods, including efficiency of screening, easily multiplexed targets and library selections, minimized resources needed to evaluate an entire DEL and large library sizes. This Review provides accounts of recently described small molecules discovered from DELs, including their initial identification, optimization and validation of biological properties including suitability for clinical applications.
Topics: Humans; Small Molecule Libraries; Drug Discovery; DNA; Ligands; Gene Library
PubMed: 37328653
DOI: 10.1038/s41573-023-00713-6 -
BioRxiv : the Preprint Server For... Sep 2023We propose to capture reaction-diffusion on a molecule-by-molecule basis from the fastest acquirable timescale, namely individual photon arrivals. We illustrate our...
We propose to capture reaction-diffusion on a molecule-by-molecule basis from the fastest acquirable timescale, namely individual photon arrivals. We illustrate our method on intrinsically disordered human proteins, the linker histone H1.0 as well as its chaperone prothymosin , as these diffuse through an illuminated confocal spot and interact forming larger ternary complexes on millisecond timescales. Most importantly, single-molecule reaction-diffusion, smRD, reveals single molecule properties without trapping or otherwise confining molecules to surfaces. We achieve smRD within a Bayesian paradigm and term our method Bayes-smRD. Bayes-smRD is further free of the average, bulk, results inherent to the analysis of long photon arrival traces by fluorescence correlation spectroscopy. In learning from thousands of photon arrivals continuous spatial positions and discrete conformational and photophysical state changes, Bayes-smRD estimates kinetic parameters on a molecule-by-molecule basis with two to three orders of magnitude less data than tools such as fluorescence correlation spectroscopy thereby also dramatically reducing sample photodamage.
PubMed: 37732202
DOI: 10.1101/2023.09.05.556378 -
IUCrData Jul 2023The title compound, CHNO, crystallizes with ' = 2 in space group 2 with the two independent mol-ecules having almost the same conformation, differing mostly at the end...
The title compound, CHNO, crystallizes with ' = 2 in space group 2 with the two independent mol-ecules having almost the same conformation, differing mostly at the end of the butanamide chain. A local inversion center near 1/8, 3/4, relates the two mol-ecules, as is common for structures in this space group with ' = 2. The mol-ecule crystallizes as the keto tautomer, and the β-diketone moieties are twisted out of planarity, with O-C⋯C-O pseudo torsion angles of -74.4 (5) and -83.9 (5)°. The N-H group of each independent mol-ecule donates an inter-molecular hydrogen bond to an amide carbonyl oxygen atom by positive or negative translations along the axis, thus forming anti-parallel chains propagating in the [010] direction.
PubMed: 37937129
DOI: 10.1107/S2414314623005655 -
IUCrData Jan 2024The equimolar and hydro-chloric acid-catalysed reaction between -jasmone and 4-methyl-thio-semicarbazide in ethano-lic solution yields the title compound, CHNS (common...
The equimolar and hydro-chloric acid-catalysed reaction between -jasmone and 4-methyl-thio-semicarbazide in ethano-lic solution yields the title compound, CHNS (common name: -jasmone 4-methyl-thio-semicarbazone). Two mol-ecules with all atoms in general positions are present in the asymmetric unit. In one of them, the carbon chain is disordered [site occupancy ratio = 0.821 (3):0.179 (3)]. The thio-semicarbazone entities [N-N-C(=S)-N] are approximately planar, with the maximum deviation from the mean plane through the selected atoms being -0.0115 (16) Å (r.m.s.d. = 0.0078 Å) for the non-disordered mol-ecule and 0.0052 (14) Å (r.m.s.d. = 0.0031 Å) for the disordered one. The mol-ecules are not planar, since the jasmone groups have a chain with -hybridized carbon atoms and, in addition, the thio-semicarbazone fragments are attached to the respective carbon five-membered rings and the dihedral angles between them for each mol-ecule amount to 8.9 (1) and 6.3 (1)°. In the crystal, the mol-ecules are connected through pairs of N-H⋯S and C-H⋯S inter-actions into crystallographically independent centrosymmetric dimers, in which rings of graph-set motifs (8) and (7) are observed. A Hirshfeld surface analysis indicates that the major contributions for the crystal cohesion are from H⋯H (70.6%), H⋯S/S⋯H (16.7%), H⋯C/C⋯H (7.5%) and H⋯N/N⋯H (4.9%) inter-actions [considering the two crystallographically independent mol-ecules and only the disordered atoms with the highest s.o.f. for the evaluation].
PubMed: 38322031
DOI: 10.1107/S2414314624000130 -
IUCrData Oct 2023The racemic mixture of the title compound, CHNOS, crystallizes in space group with two homochiral mol-ecules in each asymmetric unit. The seven-membered ring in both...
The racemic mixture of the title compound, CHNOS, crystallizes in space group with two homochiral mol-ecules in each asymmetric unit. The seven-membered ring in both mol-ecules is in a pucker-chair conformation. The extended structure exhibits C-H⋯O hydrogen bonds, of which two connect crystallographically independent mol-ecules to generate a chain propagating along the axis direction. One C-H grouping of the cyclo-propyl ring is in close contact with the phenyl ring of the neighboring independent mol-ecule in C-H⋯π type inter-actions with carbon atom-ring-centroid distances of 3.544 (5) and 3.596 (4) Å. Other inter-actions are of the parallel-reciprocal type, with the chiral carbon atom of one mol-ecule donating a proton to an oxygen atom of the sulfone group of a symmetry-related mol-ecule and . Symmetry-related mol-ecular pairs also exhibit T-type inter-actions between aromatic rings with inter-planar angles of 74.2 (2) and 69.2 (2)° and inter-centroid distances of 4.965 (4) and 5.114 (4) Å.
PubMed: 37936592
DOI: 10.1107/S2414314623009379