Drug discovery and optimization based on the co-crystal structure of natural product with target.

Due to their structural diversities and prevalent biological activities, natural products (NPs) are momentous resources for drug discovery. Although NPs have a wide range of biological activities, many exhibit structural complexity that leads to synthetic difficulties, which combines with inefficient biological activity, toxicity, and unfavorable pharmacokinetic characteristics and ultimately imparts poor safety and efficacy outcomes. Progress in crystallization and computational techniques allow crystallography to have a seasonable influences on drug discovery. By co-crystallizing with proteins, therapeutic targets of NPs in specific diseases can be identified. By analyzing the co-crystal information, the structure-activity relationships (SARs) of NPs targeting specific proteins can be grasped. Under the guidance of co-crystal information, directional structural modification and simplification are powerful strategies for overcoming limitations of NPs, improving the success rate of NP-based drug discovery, and obtaining NP-based drugs with high selectivity, low toxicity and favorable pharmacokinetic characteristics. Here, we review the co-crystal information of a selection of NPs, focusing on the SARs of NPs reflected by co-crystal information and the modification and simplification strategies of NPs, and discuss how to apply co-crystal information in the optimization of NP-based lead compound.

Novel 2-phenyl-4H-chromen derivatives: synthesis and anti-inflammatory activity evaluation in vitro and in vivo.

It is significant to design, synthesise and optimise flavonoid derivatives with better anti-inflammatory activity. This study aims to design and synthesise a series of novel 2-phenyl-4H-chromen-4-one compounds with anti-inflammatory; among them, compound 8 was discovered as the best one. And then, the effects of compound 8 on the TLR4/MAPK signalling pathway was carried out in vivo, the results indicated that compound 8 could downregulate NO, IL-6, and TNF-α expression, and suppress LPS-induced inflammation by inhibiting the TLR4/MAPK pathways. Furthermore, compound 8 reduced inflammation by a mouse model of LPS-induced inflammatory disease in vivo. The results suggest that compound 8 has the potential against inflammation through regulating TLR4/MAPK pathway and can be assessed further for drug development.

Non-peptidyl non-covalent cathepsin C inhibitoEEr bearing a unique thiophene-substituted pyridine: Design, structure-activity relationship and anti-inflammatory activity in vivo.

Cathepsin C (Cat C) is involved in inflammation regulation by activating neutrophil serine proteases (NSPs). Therefore, Cat C is an attractive target for treatment of inflammatory diseases mediated by NSPs overactivation. In previous study, compounds 54 and 77 were reported to be the first non-peptidyl non-covalent Cat C inhibitors, with good enzyme inhibitory activity and NSPs activation inhibition, but their pharmacokinetic (PK) properties were unsatisfactory. In this study, starting from 77, after several rounds of structure-based design and modification, compound SF38, a novel Cat C inhibitor bearing a unique thiophene structure was identified, which exhibited strong inhibitory activity against Cat C (IC50 = 59.9 nM). Further mechanism study and in vivo evaluation showed that SF38 inhibited the Cat C activity in bone marrow and blood, decreased the activation of NSPs, and exhibited anti-inflammatory activity in an animal model of acute lung injury, with acceptable PK properties (F = 42.07%). These results enriched the structure-activity relationship (SAR) of Cat C inhibitor with thiophene structure characteristic, and proved the broad prospect of non-peptidyl non-covalent Cat C inhibitor.

An epileptic focus location method based on ECoG.

Epilepsy is a neurological disorder characterized by the sudden abnormal discharging of brain neurons that can lead to encephalographic (EEG) abnormalities. In this study, data was obtained from epileptic patients with intracranial depth electrodes and analyzed using wavelet entropy algorithms in order to locate the epileptic foci. Significant increases in the wavelet entropy of the epileptic signals were identified during multiple episodes of clinical seizures. The results indicated that the algorithm was capable of identifying entropy changes in the epileptic sources. Furthermore, the correlations among the electrocorticogram (ECoG) signals of different channels determined using the amplitude-amplitude coupling method verified that the epileptic foci exhibited significantly higher coupling strengths. Thus, cross frequency coupling (CFC) could be an inspiration to energy and signal transitive mode of seizure and, thereby, improve diagnostic processes.