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Probing druggability on Interface and its Allosteric Regulation Mechanism on Drug Screening for CXCR4 Homodimer

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Probing Druggability on Interface and its Allosteric Regulat...

A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization

2019中国化学会第十五届全国计算（机）化学学术会议

作者： Liting Shen 陈建芳 Xingyu Du Yanzhi Guo Menglong Li Xuemei Pu College of Chemistry Sichuan University 四川大学

Modulating protein-protein interactions（PPIs） with small drug-like molecules targeting it exhibits great promising in modern drug discovery. G protein-coupled receptors（GPCRs） are the largest family of targeted proteins and could form dimers in living biological cells through PPIs. However, compared to drug development of the orthosteric site, there has been lack of investigations on the druggability of the PPI interface for GPCRs and its functional implication on experiments. Thus, in order to address these issues, we constructed a novel computational strategy, which involved in molecular dynamics simulation, virtual screening and protein structure network（PSN）, to study one representative GPCR homodimer（CXCR4）. One druggable pocket was identified in the PPI interface and one small molecule targeting it was screened, which could strengthen PPI mainly through hydrophobic interaction between the benzene rings of the PPI molecule and TM4 of the receptor. The PSN results further reveals that the PPI molecule could increase the number of the allosteric regulation pathways between the druggable pocket of the dimer interface to the orthostatic site for the subunit A but only play minor role for the other subunit B, leading to the asymmetric change in the volume of the binding pockets for the two subunits（increase for the subunit A and minor change for the subunit B）. Consequently, the screening performance of the subunit A to the antagonists is enhanced while the subunit B is unchanged nearly, implying that the PPI molecule may be beneficial to enhance the drug efficacies of the antagonists. In addition, one main regulation pathway with the highest frequency was identified for the subunit A, which consists of Trp1955.34-Tyr190 ECL2-Val1965.35-Gln2005.39-Asp2626.58-Cys28 N-term, revealing their importance in the allosteric regulation from the PPI molecule. The observations from the work could provide valuable information for the development of the PPI drug-like molecule fo

关键词： Target GPCR dimer interface druggability regulation mechanism computation

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3232-3250页

作者： Ping Yu Tanwei Gu Yueyang Rao Weimin Liang Xi Zhang Huanguo Jiang Jindi Lu Jianglian She Jianmin Guo Wei Yang Yonghong Liu Yingfeng Tu Lan Tang Xuefeng Zhou Guangdong Provincial Key Laboratory of New Drug Screening Guangdong-Hong Kong-Macao Joint Laboratory for New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology Guangdong Key Laboratory of Marine Materia MedicaSouth China Sea Institute of OceanologyChinese Academy of SciencesGuangzhou 510301China NMPA Key Laboratory for Research and Evaluation of Drug Metabolism School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Guangdong Lewwin Pharmaceutical Research Institute Co. Ltd.Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and ResearchGuangdong Engineering Research Center for Innovative Drug Evaluation and ResearchGuangzhou 510990China

Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its *** study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)***,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS *** to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed *** developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 *** encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,*** main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated *** summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.

关键词： Acute kidney injury Piericidin glycoside Peroxiredoxin 1 Nanodrug Kim-1 targeted ADME Marine drug druggability

Sinomenine derivatives with embedment of nitrogen-containing heterocycles exhibiting potent TNF-inhibitory activity

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Science China Chemistry 2012年第12期55卷 2537-2547页

作者： WANG Meng MA LiYan LOU YangTong BIAN Chao ZHOU TingTing ZHOU HaiBin LIAO HongZe MA Zhao YIN DongSheng CHEN AiZhong WANG ShaoZhong YANG ZhenYu SUN Bing YAO ZhuJun State Key Laboratory of Coordination Chemistry and Nanjing National Laboratory of Microstructures Institute of Chemical Biology and Drug InnovationSchool of Chemistry and Chemical EngineeringNanjing UniversityNanjing 210093China Shanghai Institute of Biochemistry and Cell Biology Shanghai Institutes of BiologicalSciencesChinese Academy of SciencesShanghai 200031China State Key Laboratory of Bioorganic and Natural Products Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China

Inhibitory effect on tumor necrosis factor-c~ （TNF-c0 production by sinomenine derivatives with embedment of small drug-like nitrogen hetereocyclic moieties has been studied in this work. Several new sinomenine derivatives having chlorophenyl sub- stituent have been found to exhibit much more potent TNF-a inhibitory activity than natural sinomenine and other derivatives.

关键词： sinomenine druggability heterocycle tumor necrosis factor-m inhibition

Structural Modification Based on Natural Products Leads to More Drug-like Candidates

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Chinese Journal of Structural Chemistry 2017年第12期36卷 1947-1960页

作者：陈河如张潮蒋真磊刘杰 Institute of Traditional Chinese Medicine and Natural Products College of Pharmacy Jinan University Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research Jinan University

Natural products are characterized with diverse structures and biological activities. They show a certain degree of adaptability to human beings. However, they need to be modified to increase their druggability. Several strategies including pharmacophore similarity, physicochemical property optimization, and bioactivity focus may help to make them more drug-like candidates.

关键词： natural product druggability pharmacophore similarity bioactivity focus

Strategies for translating proteomics discoveries into drug discovery for dementia

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Neural Regeneration Research 2024年第1期19卷 132-139页

作者： Aditi Halder Eleanor Drummond School of Medical Sciences and Brain&Mind Center University of SydneyNSWSydneyAustralia Department of Aged Care Prince of Wales HospitalSydneyNSWAustralia

Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia *** there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing *** such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug *** this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired *** highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this *** propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.

关键词： Alzheimer's disease biomarkers drug development drug discovery druggability frontotemporal dementia interactome proteomics tau tauopathies therapeutics

Predicted essential proteins of Plasmodium falciparum for potential drug targets

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Asian Pacific Journal of Tropical Medicine 2012年第5期5卷 352-354页

作者： Qing-Feng He Li Deng Qin-Ying Xu Zheng Shao Department of Parasitology Guangdong Medical College

Objective:To identify novel drug targets for treatment of Plasmodium ***: Local *** were used to find the proteins non-homologous to human essential proteins as novel drug *** domains of novel drug targets were identified by InterPro and Pfam.3D structures of potential drug targets were predicated by the SWISS-MODEL workspace. Ligands and ligand-binding sites of the proteins were searched by ***:Three essential proteins were identified that might be considered as potential drug ***37254.1 belonged to 1-deoxy-D-xylulose 5-phosphate reductoisomerase,CAD50499.1 belonged to chorismale synthase,CAD51220.1 belonged to FAD binging 3 family,but the function of CAD51220.1 was *** 3D structures,ligands and ligand-binding sites of AAM37254.1 and CAD50499.1 were successfully ***:Two of these potential drug targets are key enzymes in 2-C-methyl-d-erythritol 4-phosphate pathway and shikimate pathway, which are absent in humans,so these two essential proteins are good potential drug *** function and 3D structures of CAD50499.1 is still unknown,it still need further study.

关键词： Plasmodium falciparum Essential proteins Database of essential genes druggability Potential drug targets

Recognition of Natural Products as Potential Inhibitors of COVID-19 Main Protease (Mpro): In-Silico Evidences

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Natural Products and Bioprospecting 2020年第5期10卷 297-306页

作者： Rohan R.Narkhede Ashwini V.Pise Rameshwar S.Cheke Sachin D.Shinde Department of Medicinal Chemistry National Institute of Pharmaceutical Education and Research(NIPER)RaebareliLucknow 226002India Department of Pharmaceutical Chemistry Dr.Rajendra Gode College of PharmacyMakapurMaharashtra 443101India Department of Pharmacology Shri.R.D.Bhakta College of PharmacyJalnaMaharashtra 431203India

SARS-CoV-2(2019-nCoV)emerged in 2019 and proliferated rapidly across the *** are attempting to investigate antivirals specific to COVID-19 *** 2019-nCoV and SARS-CoV utilize the same receptor of the host which is COVID-19 of the main protease(Mpro).COVID-19 caused by SARS-CoV-2 is burdensome to overcome by presently acquired antiviral *** the objective and purpose of this work was to investigate the plants with reported potential antiviral *** the aid of in silico techniques such as molecular docking and druggability studies,we have proposed several natural active compounds including glycyrrhizin,bicylogermecrene,tryptanthrine,β-sitosterol,indirubin,indican,indigo,hesperetin,crysophanic acid,rhein,berberine andβ-caryophyllene which can be encountered as potential herbal candidate exhibiting anti-viral activity against *** docking outcomes have been executed which evidenced the worthy of these selected herbal remedies for future drug development to combat coronavirus disease.

关键词： nCoV-2019 COVID-19 main protease Herbal remedies Docking study druggability

Small Molecule Dac51 Targeting FTO

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Small Molecule Dac51 Targeting FTO