Harnessing the cyclization strategy for new drug discovery

The design of new ligands with high affinity and specificity against the targets of interest has been a central focus in drug discovery.As one of the most commonly used methods in drug discovery,the cyclization represents a feasible strategy to identify new lead compounds by increasing structural novelty,scaffold diversity and complexity.Such strategy could also be potentially used for the follow-on drug discovery without patent infringement.In recent years,the cyclization strategy has witnessed great success in the discovery of new lead compounds against different targets for treating various diseases.Herein,we first briefly summarize the use of the cyclization strategy in the discovery of new small-molecule lead compounds,including the proteolysis targeting chimeras(PROTAC)molecules.Particularly,we focus on four main strategies including fused ring cyclization,chain cyclization,spirocyclization and macrocyclization and highlight the use of the cyclization strategy in lead generation.Finally,the challenges including the synthetic intractability,relatively poor pharmacokinetics(PK)profiles and the absence of the structural information for rational structure-based cyclization are also briefly discussed.We hope this review,not exhaustive,could provide a timely overview on the cyclization strategy for the discovery of new lead compounds.

FingerDTA:A Fingerprint-Embedding Framework for Drug-Target Binding Affinity Prediction

Many efforts have been exerted toward screening potential drugs for targets,and conducting wet experiments remains a laborious and time-consuming approach.Artificial intelligence methods,such as Convolutional Neural Network(CNN),are widely used to facilitate new drug discovery.Owing to the structural limitations of CNN,features extracted from this method are local patterns that lack global information.However,global information extracted from the whole sequence and local patterns extracted from the special domain can influence the drugtarget affinity.A fusion of global information and local patterns can construct neural network calculations closer to actual biological processes.This paper proposes a Fingerprint-embedding framework for Drug-Target binding Affinity prediction(FingerDTA),which uses CNN to extract local patterns and utilize fingerprints to characterize global information.These fingerprints are generated on the basis of the whole sequence of drugs or targets.Furthermore,FingerDTA achieves comparable performance on Davis and KIBA data sets.In the case study of screening potential drugs for the spike protein of the coronavirus disease 2019(COVID-19),7 of the top 10 drugs have been confirmed potential by literature.Ultimately,the docking experiment demonstrates that FingerDTA can find novel drug candidates for targets.All codes are available at http://lanproxy.biodwhu.cn:9099/mszjaas/FingerDTA.git.

Antiviral Activity of Medicinal Plants against Human Coronavirus: a systematic scoping review of in vitro and in vivo experimentations

OBJECTIVE:To investigate the in vitro and in vivo studies of natural compounds and medicinal plants with anti-coronavirus activity.METHODS:A systematic review was performed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Animal Research:Reporting of in vivo experiments guidelines to find data for medicinal plants and natural products effective against human coronaviruses in in vitro or in vivo studies.Studies published up to September 6,2020 were included.Studies(in vitro or in vivo)reporting the effect of medicinal plants and natural products or their derivatives on human coronavirus were included RESULTS:Promising anti-coronavirus effects are seen with different herbal compounds like some diterpenoids,sesquiterpenoids,and three compounds in tea with 3 CLpro inhibiting effect of Severe Acute Respiratory Syndrome Coronavirus(SARS-Co V);Hirsutenone,Six cinnamic amides and bavachinin are PLpro inhibitors and Tanshinones are active on both 3 CLpro and PLpro.Some flavonoid compounds of Citrus fruits act on Immunoregulation and target angiotensin-converting enzyme 2 which is used by SARS-COV for entry.Virus helicase is possibly inhibited by two compounds myricetin and scutellarein.CONCLUSION:This review shows that complementary medicine have the potential for new drug discovery against coronavirus.Further research is needed before definitive conclusions can be made concerning the safety and efficacy of the use of these medicinal plants.