The advent of focused library and virtual screening has reduced the disadvantage of combinatorial chemistry and changed it to a realizable and cost-effective tool in drug discovery. Usually, genetic algorithms (GAs) are used to quickly finding high-scoring molecules by sampling a small subset of the total combinatorial space. Therefore, scoring functions play essential roles in focused library design. Reported here is our initial attempt to establish a new approach for generating a target-focused library using the combination of the scores of structural diversity and binding affinity with our newly improved drug-likeness scoring functions. Meanwhile, a software package, named LD1.0, was developed on the basis of the new approach. One test on a cyclooxygenase (COX)2-focused library successfully reproduced the structures that have been experimentally studied as COX2-selective inhibitors. Another test is on a peroxisome proliferator-activated receptors gamma-focused library design, which not only reproduces the key fragments in the approved (thiazolidinedione) TZD drugs, but also generates some new structures that are more active than the approved drugs or published ligands. Both of the two tests took approximately 15% of the running time of the ordinary molecular docking method. Thus, our new approach is an effective, reliable, and practical way for building up a properly sized focused library with a high hit rate, novel structure, and good ADME/T profile.

Revealing and characterizing the catalytic sites, along with elucidating a convenient activity descriptor, can provide essential guidance in determining efficient electrocatalytic catalysts for the CO2 reduction reaction (CO2RR). In this work, the mechanism of CO2 reduction to methane (CH4) on 23 transition metal-coordinated nitrogen-doped carbon M–N4–C single-atom catalysts (SACs) was studied by density functional theory calculations, a step forward to revealing the effects of the axial O atom (M–N4O–C) on their catalytic activity. The electrocatalytic reduction activity of CO2 over M–N4–C SACs is strongly dependent on the outmost d-shell electron numbers and electronegativity of the selected metals. The introduction of the axial O atom changes the coordination structure of the central metal atoms, which not only improves the stability of M–N4O–C SACs (especially electrochemical stability) but also affects the adsorption strength of intermediate species and then improves or reduces the catalytic activity, which depends on the intrinsic properties of the metal atoms. More importantly, by considering the comprehensive effects of the number of outmost d-shell electrons, the electronegativity, coordinate numbers, and bonding length of the central metal atom and the nearest neighbor atom, a descriptor (φ) based on the intrinsic properties of materials was developed to correlate the catalytic activity. The volcano-shaped relationships between the φ and limiting potentials were well established. In particular, five SACs (Mn–N4–C, Cr–N4–C, Os–N4O–C, Ru–N4O–C, and Rh–N4O–C) close to the summit of the volcano were screened. Based on this descriptor, the catalyst activity can be predicted directly from the characteristics of the material instead of the expensive calculation of adsorption energies. This work is of great significance for understanding the mechanism of electrocatalytic CO2RR and the design of efficient and stable electrocatalysts.