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Accumulated evidence suggests that binding kinetic properties—especially dissociation rate constant or drug-target residence time—are crucial factors affecting drug potency. However, quantitative prediction of kinetic properties has always been a challenging task in drug discovery. In this study, the VolSurf method was successfully applied to quantitatively predict the koff values of the small ligands of heat shock protein 90α (HSP90α), adenosine receptor (AR) and p38 mitogen-activated protein kinase (p38 MAPK). The results showed that few VolSurf descriptors can efficiently capture the key ligand surface properties related to dissociation rate; the resulting models demonstrated to be extremely simple, robust and predictive in comparison with available prediction methods. Therefore, it can be concluded that the VolSurf-based prediction method can be widely applied in the ligand-receptor binding kinetics and de novo drug design researches.

Although mAbs targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway have achieved remarkable therapeutic potential against multiple types of cancer, it is still of great interest for researchers to develop small-molecule PD-1/PD-L1 inhibitors without the mAb-related disadvantages of no oral bioavailability and poor solid tumor penetration. However, targeting the PD-1/PD-L1 pathway with small molecules is normally considered challenging because of the flat and large interaction surface of the PD-1/PD-L1 complex. In this paper, a total of 2558 PD-1/PD-L1 inhibitors were compiled from recent patents and literatures and then used for exploring the chemical space and structural features of PD-1/PD-L1 inhibitors by partial least-squares discriminant analysis. The results showed that intramolecular H bond, amphotericity indices, radius of gyration, nonbond electrostatic energy, fractional van der Waals surface area of H-bond donors, octanol–water partition coefficient, and molecular weight are the seven key features discriminating the PD-1/PD-L1 inhibitors from noninhibitors, with the prediction accuracy larger than 0.90. Based on the seven crystal structures of the PD-L1 dimer complexed with the patent Bristol Myers Squibb (BMS) inhibitors, the feasibility of molecular docking for this unconventional binding pocket was further investigated. The results showed that the ensemble-based flexible docking protocol can reproduce the near-native binding conformations of the BMS inhibitors with a strong correlation between the IC 50 values and ligand–receptor interaction energies ( R = 0.81). In general, this paper delineates, for the first time, the characteristic features of the PD-1/PD-L1 inhibitors as well as a high-quality flexible docking strategy for the unconventional binding pocket of the PD-L1 dimer.

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Due to the potencies in the treatments of cancer, infectious diseases, and autoimmune diseases, the developments of human TLR8 (hTLR8) agonists and antagonists have attracted widespread attentions. The hTLR8 agonists and antagonists have similar structures but with completely opposite biological effects. Up to date, the subtle differences in the structures between the hTLR8 agonists and antagonists are still unknown. In this work, emerging chemical pattern (ECP) was successfully used to extract the key chemical patterns of the hTLR8 agonists and antagonists. By using CAEP classifier, an optimal ECP model with only 3 descriptors was established with the overall prediction accuracy larger than 90%. Further hierarchical cluster analysis and molecular docking showed that the H-bond and hydrophobic properties are the key features distinguishing the hTLR8 agonists from antagonists. Comparing with the antagonists, the agonists show stronger specific H-bond properties, while antagonists have stronger non-specific hydrophobic properties. The significant differences in the structural properties may be closely related to the activation/inhibition mechanism of hTLR8. K E Y W O R D Sagonist, antagonist, emerging chemical pattern, prediction, toll-like receptor 8