827 results match your criteria dhfr inhibitors


Hydrazonoyl bromide precursors as DHFR inhibitors for the synthesis of bis-thiazolyl pyrazole derivatives; antimicrobial activities, antibiofilm, and drug combination studies against MRSA.

Bioorg Chem 2021 Sep 13;116:105339. Epub 2021 Sep 13.

Chemistry Department, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt. Electronic address:

Microbial resistance is a big concern worldwide, making the development of new antimicrobial drugs difficult. The thiazole and pyrazole rings are important heterocyclic compounds utilized to produce a variety of antimicrobial medications. As a result, a series of new bis-thiazolyl-pyrazole derivatives 3, 4a-c, 5a, b, and 6a-c was synthesized by reacting bis hydrazonoyl bromide with several active methylene reagents in a one-pot reaction. Read More

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September 2021

: A Novel Prognostic Marker in Canine Melanoma and a Predictive Marker for Resistance to CDK4/6 Inhibitor Treatment.

Front Vet Sci 2021 16;8:705359. Epub 2021 Aug 16.

Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.

Uncontrolled proliferation is a key feature of tumor progression and malignancy. This suggests that cell-cycle related factors could be exploited as cancer biomarkers and that pathways specifically involved in the cell cycle, such as the Rb-E2F pathway, could be targeted as an effective anti-tumor therapy. We investigated 34 formalin-fixed paraffin-embedded (FFPE) tissue samples of canine cutaneous melanocytoma, cutaneous melanoma, and oral melanoma. Read More

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Phytochemical constituents of as potential inhibitors of dihydrofolate reductase: A strategic approach against shigellosis.

J Biomol Struct Dyn 2021 Aug 23:1-16. Epub 2021 Aug 23.

Faculty of Arts and Sciences, Department of Chemistry, Gaziantep University, Gaziantep, Turkey.

type 1 is considered as an epidemic in different developing countries, which is responsible for the most severe form of bacterial dysentery. It habitually can develop to the most severe form of dysentery with deadly complications. Development of drugs against this disease is still ongoing. Read More

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3-Methyl-imidazo[2,1-b]thiazole derivatives as a new class of antifolates: Synthesis, in vitro/in vivo bio-evaluation and molecular modeling simulations.

Bioorg Chem 2021 Jul 24;115:105205. Epub 2021 Jul 24.

Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.. Electronic address:

Inhibiting the Dihydrofolate reductase (DHFR) enzyme has been validated in multiple clinical manifestations related to bacterial infection, malaria, and multiple types of cancer. Herein, novel series of 3-methyl-imidazo[2,1-b] thiazole-based analogs were synthesized and biologically evaluated for their in vitro inhibitory profile towards DHFR. Compounds 22 and 23 exhibited potent inhibitory profile targeting DHFR (IC 0. Read More

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Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Pteridine Reductase and Dihydrofolate Reductase.

Pharmaceuticals (Basel) 2021 Jun 30;14(7). Epub 2021 Jun 30.

Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

and parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to (), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine-nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. Read More

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Potency boost of a dihydrofolate reductase inhibitor by multienzyme FH-dependent reduction.

Proc Natl Acad Sci U S A 2021 Jun;118(25)

Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110;

Triaza-coumarin (TA-C) is a (Mtb) dihydrofolate reductase (DHFR) inhibitor with an IC (half maximal inhibitory concentration) of ∼1 µM against the enzyme. Despite this moderate target inhibition, TA-C shows exquisite antimycobacterial activity (MIC, concentration inhibiting growth by 50% = 10 to 20 nM). Here, we investigated the mechanism underlying this potency disconnect. Read More

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Dye degradation, antibacterial and in-silico analysis of Mg/cellulose-doped ZnO nanoparticles.

Int J Biol Macromol 2021 Aug 19;185:153-164. Epub 2021 Jun 19.

Department of Physics, Riphah Institute of Computing and Applied Sciences (RICAS), Riphah International University, 14 Ali Road, Lahore, Pakistan.

Various concentrations of Mg into fixed amount of cellulose nanocrystals (CNC)-doped ZnO were synthesized using facile chemical precipitation. The aim of present study is to remove dye degradation of methylene blue (MB) and bactericidal behavior with synthesized product. Phase constitution, functional group analysis, optical behavior, elemental composition, morphology and microstructure were examined using XRD, FTIR, UV-Vis spectrophotometer, EDS and HR-TEM. Read More

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Structural Insights of Three 2,4-Disubstituted Dihydropyrimidine-5-carbonitriles as Potential Dihydrofolate Reductase Inhibitors.

Molecules 2021 May 29;26(11). Epub 2021 May 29.

Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

In this report, we describe the structural characterization of three 2,4-disubstituted-dihydropyrimidine-5-carbonitrile derivatives, namely 2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-4-propyl-1,6-dihydropyrimidine-5-carbonitrile , 4-(2-methylpropyl)-2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-1,6-dihydropyrimidine-5-carbonitrile , and 2-[(2-ethoxyethyl)sulfanyl]-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitrile monohydrate . An X-ray diffraction analysis revealed that these compounds were crystallized in the centrosymmetric space groups and adopt an L-shaped conformation. One of the compounds () crystallized with a water molecule. Read More

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Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents.

Int J Mol Sci 2021 Apr 1;22(7). Epub 2021 Apr 1.

Department of Organic Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland.

Eighteen previously undescribed trimethoprim (TMP) analogs containing amide bonds () were synthesized and compared with TMP, methotrexate (MTX), and netropsin (NT). These compounds were designed as potential minor groove binding agents (MGBAs) and inhibitors of human dihydrofolate reductase (DHFR). The all-new derivatives were obtained via solid phase synthesis using 4-nitrophenyl Wang resin. Read More

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Combined gene deletion of dihydrofolate reductase-thymidylate synthase and pteridine reductase in Leishmania infantum.

PLoS Negl Trop Dis 2021 04 27;15(4):e0009377. Epub 2021 Apr 27.

Axe des Maladies Infectieuses et Immunitaires du Centre de Recherche du CHU de Québec, Centre de recherche en Infectiologie, and Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Québec City, Canada.

Our understanding of folate metabolism in Leishmania has greatly benefited from studies of resistance to the inhibitor methotrexate (MTX). Folates are reduced in Leishmania by the bifunctional dihydrofolate reductase thymidylate synthase (DHFR-TS) and by pteridine reductase (PTR1). To further our understanding of folate metabolism in Leishmania, a Cos-seq genome-wide gain of function screen was performed against MTX and against the two thymidylate synthase (TS) inhibitors 5-fluorouracil and pemetrexed. Read More

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Identification of selective DHFR inhibitors using quantum chemical and molecular modeling approach.

J Biomol Struct Dyn 2021 Apr 27:1-9. Epub 2021 Apr 27.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.

Among the various known targets for the treatment of Leishmaniasis, dihydrofolate reductase (DHFR) is an essential target which plays an important role in the folate metabolic pathway. In the current study, pharmacoinformatics approaches including quantum chemistry methods, molecular docking and molecular dynamics simulations have been utilized to identify selective DHFR (DHFR) inhibitors. Initially, for the design of new DHFR inhibitors, a virtual combinatorial library was created by considering various head groups (scaffolds), linkers and tail groups. Read More

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Geographical spread and structural basis of sulfadoxine-pyrimethamine drug-resistant malaria parasites.

Int J Parasitol 2021 Jun 26;51(7):505-525. Epub 2021 Mar 26.

Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India; National Institute of Malaria Research, Dwarka, New Delhi, India. Electronic address:

The global spread of sulfadoxine (Sdx, S) and pyrimethamine (Pyr, P) resistance is attributed to increasing number of mutations in DHPS and DHFR enzymes encoded by malaria parasites. The association between drug resistance mutations and SP efficacy is complex. Here we provide an overview of the geographical spread of SP resistance mutations in Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) encoded dhps and dhfr genes. Read More

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2-Substituted-mercapto-quinazolin-4(3H)-ones as DHFR inhibitors.

Mini Rev Med Chem 2021 Mar 3. Epub 2021 Mar 3.

Department of Medicinal Chemistry, College of Pharmacy, Mansoura University, Mansoura 35516. Egypt.

Antifolates are a class of drugs used as antibacterial, antiparasitic, and anticancer agents. This review focuses on 2-substituted-mercapto-quinazolin-4(3H)-one analogues as dihydrofolate reductase (DHFR) inhibitors. Several research efforts have concluded a structural model for this class of 2-thio-quinazoline derivatives to get compounds with remarkable biological activity. Read More

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A novel bicyclic 2,4-diaminopyrimidine inhibitor of dihydrofolate reductase.

PeerJ 2021 3;9:e10743. Epub 2021 Feb 3.

Biosensing and Bioprospecting Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand.

is a Gram-positive bacterial pathogen of pigs and an emerging zoonotic pathogen. It has become increasingly resistant to multiple classes of antibiotics. New drug candidates and knowledge of their targets are needed to combat antibiotic-resistant . Read More

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February 2021

Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors.

Antibiotics (Basel) 2021 Feb 5;10(2). Epub 2021 Feb 5.

Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt.

Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide -, pyridine-2-one -, and 2-imino-2-chromene-3-carboxamide , derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, , , , , , and , revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. Read More

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February 2021

Synthesis, pharmacological evaluation and Molecular modelling studies of pregnenolone derivatives as inhibitors of human dihydrofolate reductase.

Steroids 2021 04 5;168:108801. Epub 2021 Feb 5.

Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, 22060 Abbottabad, KP, Pakistan. Electronic address:

In current study, we synthesized chalcone derivatives (13a-c) via base-catalyzed Claisen-Schmidt condensation reaction. We further treated diamino compounds with synthesized chalcones to produce 3,4-dihydropyrimidin-2(1H)-one (18a-c), 3,4-dihydropyrimidin-2(1H)-thione (19a-c) and 2-aminopyrimidine (20a-c) derivatives of pregnenolone by cyclization reaction. Cell viability test of synthesized steroidal chalcones and their pyrimidine and thiopyrimidine derivatives against human breast (MCF-7), human lung (A549) and human prostate (PC-3) cancer cell lines was performed using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), assay. Read More

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Discovery of new non-pyrimidine scaffolds as DHFR inhibitors by fragment-based screening.

J Enzyme Inhib Med Chem 2021 Dec;36(1):198-206

National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathumthani, Thailand.

In various malaria-endemic regions, the appearance of resistance has precluded the use of pyrimidine-based antifolate drugs. Here, a three-step fragment screening was used to identify new non-pyrimidine dihydrofolate reductase (DHFR) inhibitors. Starting from a 1163-fragment commercial library, a two-step differential scanning fluorimetry screen identified 75 primary fragment hits. Read More

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December 2021

Identification of the Competing Endogenous RNA Networks in Oxidative Stress Injury of Melanocytes.

DNA Cell Biol 2021 Feb 20;40(2):192-208. Epub 2021 Jan 20.

Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China.

Competing endogenous RNAs (ceRNAs), including long noncoding RNA (lncRNA), circular RNA (circRNA), pseudogenes, synthetic miRNA inhibitors, etc. are classes of RNAs that can compete and interact with each other within an organism. There are regions in these RNAs that can be bound by messenger-RNA-interfering complementary RNA (microRNA), called microRNA response elements (MREs). Read More

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February 2021

Electronic properties investigation of human dihydrofolate reductase complexes with ligands.

J Biomol Struct Dyn 2020 Dec 21:1-16. Epub 2020 Dec 21.

Department of Chemistry, College of Science, Deanship of Scientific Research, Taif University, Taif, Saudi Arabia.

Despite the fact that there are already drugs for cancer, they still show strong toxicity to the human organism. That is why it is necessary to establish the factors affecting activity in order to develop new, more effective drugs aimed at tumor cells, minimizing harm to healthy cells. The present research is based on electronic properties calculation of the complexes using AlteQ approach. Read More

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December 2020

Distal Regions Regulate Dihydrofolate Reductase-Ligand Interactions.

Methods Mol Biol 2021 ;2253:185-219

Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ, USA.

Protein motions play a fundamental role in enzyme catalysis and ligand binding. The relationship between protein motion and function has been extensively investigated in the model enzyme dihydrofolate reductase (DHFR). DHFR is an essential enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Read More

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Integron mediated antimicrobial resistance in diarrheagenic Escherichia coli in children: in vitro and in silico analysis.

Microb Pathog 2021 Jan 7;150:104680. Epub 2020 Dec 7.

Department of Microbiology, University College of Medical Sciences & GTB Hospital (University of Delhi), Delhi, India. Electronic address:

The exchange of genes between bacterial chromosome and plasmid(s) and their integration into integrons are mainly responsible for acquisition and dissemination of antibiotic resistance. We investigated the role of integrons and their underlying molecular mechanisms leading to development of adaptability in E. coli and eventual resistance to antimicrobials. Read More

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January 2021

In Ovo and In Silico Evaluation of the Anti-Angiogenic Potential of Syringin.

Drug Des Devel Ther 2020 25;14:5189-5204. Epub 2020 Nov 25.

The Graduate School, University of Santo Tomas, Manila 1015, Philippines.

Introduction: Cancer is considered as one of the deadliest human diseases today. Angiogenesis, the propagation of new blood vessels from pre-existing vasculature, is a critical step in the progression of cancer as it is essential in the growth and metastasis of tumors. Hence, suppression of angiogenesis is a promising approach in cancer therapy. Read More

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Exploring the ability of dihydropyrimidine-5-carboxamide and 5-benzyl-2,4-diaminopyrimidine-based analogues for the selective inhibition of L. major dihydrofolate reductase.

Eur J Med Chem 2021 Jan 4;210:112986. Epub 2020 Nov 4.

Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, 22060, Pakistan. Electronic address:

To tackle leishmaniasis, search for efficient therapeutic drug targets should be pursued. Dihydrofolate reductase (DHFR) is considered as a key target for the treatment of leishmaniasis. In current study, we are interested in the design and synthesis of selective antifolates targeting DHFR from L. Read More

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January 2021

Hemisyntheses and In-silico Study of New Analogues of Carlina Oxide from Carthamus Caeruleus Roots.

Comb Chem High Throughput Screen 2021 ;24(9):1503-1513

Laboratoire des Substances Naturelles et Bioactives (LASNABIO), Université de Tlemcen, BP 119, 13000, Chetouane, Algeria.

Aim And Objective: Nowadays, developing effective antibiotics for bacterial control has become difficult due to increased resistance to the available medicines in the market. Essential oils possess interesting biological properties as some of their components have very powerful antiviral and antibacterial properties. Carthamus caeruleus is a plant that has antibacterial and antioxidant activity due to the presence of an acetylenic compound, Carlina oxide. Read More

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January 2021

Stress fiber anisotropy contributes to force-mode dependent chromatin stretching and gene upregulation in living cells.

Nat Commun 2020 09 29;11(1):4902. Epub 2020 Sep 29.

Department of Mechanical Science and Engineering, The Grainger College of Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.

Living cells and tissues experience various complex modes of forces that are important in physiology and disease. However, how different force modes impact gene expression is elusive. Here we apply local forces of different modes via a magnetic bead bound to the integrins on a cell and quantified cell stiffness, chromatin deformation, and DHFR (dihydrofolate reductase) gene transcription. Read More

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September 2020

Mutational analysis confirms the presence of distal inhibitor-selectivity determining residues in B. stearothermophilus dihydrofolate reductase.

Arch Biochem Biophys 2020 10 15;692:108545. Epub 2020 Aug 15.

Dept. of Chemistry & Biochemistry, Montclair State University, Montclair, NJ, 07043, USA. Electronic address:

Many antibacterial and antiparasitic drugs work by competitively inhibiting dihydrofolate reductase (DHFR), a vital enzyme in folate metabolism. The interactions between inhibitors and DHFR active site residues are known in many homologs but the contributions from distal residues are less understood. Identifying distal residues that aid in inhibitor binding can improve targeted drug development programs by accounting for distant influences that may be less conserved and subject to frequent resistance causing mutations. Read More

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October 2020

Histone deacetylase inhibition enhances the therapeutic effects of methotrexate on primary central nervous system lymphoma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa084. Epub 2020 Jul 3.

Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan.

Background: Polyglutamylation is a reversible protein modification that commonly occurs in tumor cells. Methotrexate (MTX) in tumor cells is polyglutamylated and strongly binds to dihydrofolate reductase (DHFR) without competitive inhibition by leucovorin. Therefore, tumor cells with high polyglutamylation levels are supposed to be selectively killed, whereas normal cells with lower polyglutamylation are rescued by leucovorin. Read More

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Three Alkaloids from an Apocynaceae Species, as Antileishmaniasis Agents by In Silico Demo-case Studies.

Plants (Basel) 2020 Aug 3;9(8). Epub 2020 Aug 3.

Molecular Biology and Genetics, Department of Biochemistry, Faculty of Sciences, University of Extremadura, 06006 Badajoz, Spain.

This paper is focused on demonstrating with a real case that Ethnobotany added to Bioinformatics is a promising tool for new drugs search. It encourages in silico investigation of "challua kaspi", a medicinal kichwa Amazonian plant ( against a Neglected Tropical Disease, leishmaniasis. The illness affects over 150 million people especially in subtropical regions, there is no vaccination and conventional treatments are unsatisfactory. Read More

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Designing Dihydrofolate Reductase Inhibitors as X-ray Radiosensitizers to Reverse Radioresistance of Cervical Cancer.

ACS Med Chem Lett 2020 Jul 17;11(7):1421-1428. Epub 2020 Jun 17.

The First Affiliated Hospital and Department of Chemistry, Jinan University, Guangzhou 510632, China.

X-ray radiotherapy has been widely used in the treatment of cervical cancer, a common gynecologic malignant tumor. However, the therapeutic efficacy tends to be indistinctive. One major reason for this is amplification of the dihydrofolate reductase (DHFR) gene, which causes an increase in DHFR activity and attenuation of the treatment effect. Read More

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Antimalarial effect of cell penetrating peptides derived from the junctional region of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase.

Peptides 2020 09 13;131:170372. Epub 2020 Jul 13.

National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), 113 Thailand Science Park, Khlong Nueng, Khlong Luang, Pathum Thani, 12120, Thailand.

Dihydrofolate reductase-thymidylate synthase of Plasmodium falciparum (PfDHFR-TS) is an important target of antifolate antimalarial drugs. However, drug resistant parasites are widespread in malaria endemic regions. The unique bifunctional property of PfDHFR-TS could be exploited for the design of allosteric inhibitors that interfere with the active dimer conformation. Read More

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September 2020