Parkinson's disease (PD) is one of the most common agerelated neurodegenerative diseases. Inhibition of monoamine oxidase-B (MAO-B), which is mainly found in the glial cells of the brain, may lead to an elevated level of dopamine (DA) in patients. MAO-B inhibitors have been used extensively for patients with PD. However, the discovery of the selective MAO-B inhibitor is still a challenge. In this study, a computational strategy was designed for the rapid discovery of selective MAO-B inhibitors. A series of (S)-2-(benzylamino)propanamide derivatives were designed. In vitro biological evaluations revealed that (S)-1-(4-((3-fluorobenzyl)oxy)benzyl)azetidine-2-carboxamide (C3) was more potent and selective than safinamide, a promising drug for regulating MAO-B. Further studies revealed that the selectivity mechanism of C3 was due to the steric clash caused by the residue difference of Phe208 (MAO-A) and Ile199 (MAO-B). Animal studies showed that compound C3 could inhibit cerebral MAO-B activity and alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal loss.

Protein kinases (PKs) are important drug targets, but kinases selectivity poses a challenge to protein kinase inhibitors (PKIs) design. Fragment-based drug discovery (FBDD) has achieved great success in the discovery of highly specific PKIs. It makes full use of kinase-fragment interaction in target kinase subpockets to obtain promising selectivity. However, it's difficult to understand the complicated kinase-fragment interaction space, and systemic discussion of these interactions is still lacking. Herein, we introduce the advantages of the FBDD strategy in PKIs design. Key features of the selectivity of kinase-fragment interactions are summarized and analyzed. Some promising PKIs are introduced as case studies to help understand the fragment-to-lead (F2L) optimization process. Novel strategies and technologies for FBDD in PKIs discovery are also outlooked. PKs and their inhibitorsPKs regulate almost every aspect of cell biology due to their vital roles in cellular signaling [1]. The human genome encodes 518 kinase proteins, which catalyze the phosphorylation process by transferring the γ-phosphate moiety of adenosine triphosphate (ATP) to the hydroxyl groups of tyrosine, serine, or threonine residues of their substrates [2,3]. Because signal transduction relies on the phosphotransfer cascade, the targeting of PKs to regulate signal transduction processes could be a novel therapeutic strategy against multiple diseases [4,5]. For example, PKs have been successfully targeted to inhibit cancer cell proliferation and angiogenesis. Indeed, many recent studies have revealed that the deregulation of kinase is firmly associated with virtually all disease areas, such as inflammatory [6], degenerative [7], and cardiovascular diseases [8]. Therefore, PKs are regarded as important drug targets in many diseases. HighlightsProtein kinases inhibitors play vital roles in the treatment of multiple diseases. The problem of selectivity poses a challenge to the development of kinase inhibitors.Fragment-based drug discovery (FBDD) could maximize the kinase-fragment interaction in target kinase subpockets. And the abundant kinase-inhibitor complexes could provide necessary structural information for FBDD to obtain promising selectivity.Understanding kinase-fragment interactions in each kinase subpocket is significant for FBDD. Special interactions targeting subpockets in the back cleft or FP-I/FP-II subpockets of the front cleft are important for selectivity.Development of kinase inhibitors with novel mode of action like allosteric inhibitors via FBDD method is an efficient and potent way to achieve good selectivity.

The cullin-RING ubiquitin ligases (CRLs) are responsible for about 20% of cellular protein degradation and regulate diverse cellular processes, and the dysfunction of CRLs is implicated in human diseases. Targeting the CRLs has become an emerging strategy for the treatment of human diseases. Herein, we describe the discovery of a hit compound from our in-house library and further structure-based optimizations, which have enabled the identification of new triazolo[1,5a]pyrimidine-based inhibitors targeting the DCN1−UBC12 interaction. Compound WS-383 blocks the DCN1−UBC12 interaction (IC 50 = 11 nM) reversibly and shows selectivity over selected kinases. WS-383 exhibits cellular target engagement to DCN1 in MGC-803 cells. WS-383 inhibits Cul3/1 neddylation selectively over other cullins and also induces accumulation of p21, p27, and NRF2. Collectively, targeting the DCN1−UBC12 interaction would be a viable strategy for selective neddylation inhibition of Cul3/1 and may be of therapeutic potential for disease treatment in which Cul3/1 is dysregulated.

Protoporphyrinogen IX oxidase (PPO, E.C. 1.3.3.4), a key functional enzyme existing in various organisms, is acknowledged to be one of the most important action targets in the development of herbicides due to its pivotal roles in chlorophyll and heme biosynthesis pathways. As our persistent research work on the discovery of novel PPO-inhibiting herbicides, a new compound methyl 2- ((5-(3-chloro-4,5,6,7-tetrahydro-2H-indazol-2-yl)-6-fluorobenzo[d]thiazol-2-yl)thio)acetate (8aj, K i = 16 nM) was screened out as a hit compound via a fragment-based virtual screening method performed in the Auto Core Fragment in silico Screening web server. Subsequently, through a fused process of "hit-to-lead" optimization guided by molecular simulation, a total of 30 3-chloro-4,5,6,7-tetrahydro-2H-indazol-benzo[d]thiazole derivatives were synthesized and characterized. The results of the enzymatic inhibition bioassay showed that more than half of the newly synthesized compounds displayed higher activity against Nicotiana tabacum PPO (NtPPO) than oxadiazon, a commercial PPO-inhibiting herbicide. In particular, compound 8ab, a subnanomolar inhibitor with a K i value of 380 pM against NtPPO, was discovered, which showed to be 71-fold more active than the commercial control oxadiazon (K i = 27 nM), and was proven to be the most potent PPO inhibitor so far. Furthermore, the greenhouse assay demonstrated that most of the synthetic compounds showed good herbicidal activity toward the tested weeds. Especially, compound 8ad (K i = 670 pM) showed the most promising post-emergence herbicidal activity with a broad spectrum of weed control even at a concentration as low as 37.5 g a.i./ha and relatively safe to rice at a dosage of 150 g a.i./ha, indicating that 8ad has the greatest potential to be developed as a new herbicide for weed control in paddy fields. This work provides a paradigm for the rational design and discovery of a novel PPO-inhibiting herbicide guided by the fragment-based drug design.

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Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell activation, and targeting HPK1 is considered a promising strategy for improving responses to antitumor immune therapies. The biggest challenge of HPK1 inhibitor design is to achieve a higher selectivity to GLK, an HPK1 homology protein as a positive regulator of T-cell activation. Herein, we report the design of a series of macrocycle-based HPK1 inhibitors via a conformational constraint strategy. The identified candidate compound 5i exhibited HPK1 inhibition with an IC 50 value of 0.8 nM and 101.3-fold selectivity against GLK. Compound 5i also displayed good oral bioavailability (F = 27−49%) in mice and beagles and favorable metabolic stability (T 1/2 > 186.4 min) in human liver microsomes. More importantly, compound 5i demonstrated a clear synergistic effect with anti-PD-1 in both MC38 (MSI) and CT26 (MSS) syngeneic tumor mouse models. These results showed that compound 5i has a great potential in immunotherapy.

Lysine specific demethylase 1 (LSD1) was regarded as a promising anticancer target for the novel drug discovery. In this work, we carried out a molecular modeling study on the substituted pyridine derivatives as LSD1 inhibitors using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations. Molecular docking studies predicted the probable binding mode of ligands, and suggested Lys661 and Asp555 might be key residues. Our 3D-QSAR models exhibited satisfactory internal and external predicted capacity. For the comparative molecular field analysis (CoMFA) model, its training set had q of 0.595 and r of 0.959, while test set had q of 0.512 and r of 0.846. For the best comparative molecular similarity indices analysis (CoMSIA) model, its training set had q of 0.733 and r of 0.982, while test set had q of 0.695 and r of 0.922. MD simulations result revealed the detailed binding process and found an important conserved water-bridge motif between ligands and protein. The binding free energies calculation using Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach coincided well with the experimental bioactivity and demonstrated that the electrostatic interaction was the major driving force for binding. The energy decomposition pointed out some significant residues (Asp555, Lys661, Trp695, Tyr761 and FAD) for the LSD1 potency increase. Based on these results, five new inhibitors were designed, and their activities were predicted using our 3D-QSAR models.