Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening

Several members of the 3′,5′-cyclic nucleotide phosphodiesterase (PDE) family play an essential role in cellular processes, which has labeled them as interesting targets for various diseases. The parasitic protozoan Trypanosoma brucei, causative agent of human African trypanosomiasis, contains several cyclic AMP specific PDEs from which TbrPDEB1 is validated as a drug target. The recent discovery of selective TbrPDEB1 inhibitors has increased their potential for a novel treatment for this disease. Compounds characterized by a rigid biphenyl tetrahydrophthalazinone core structure were used as starting point for the exploration of novel TbrPDEB1 inhibitors. Using a virtual screening campaign and structure-guided design, diaryl ether substituted phthalazinones were identified as novel TbrPDEB1 inhibitors with IC50 values around 1 μM against T. brucei. This study provides important structure-activity relationship (SAR) information for the future design of effective parasite-specific PDE inhibitors.

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Chemical Starting Matter for HNF4α Ligand Discovery and Chemogenomics

International Journal of Molecular Sciences ◽

10.3390/ijms21217895 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7895

Author(s):

Isabelle Meijer ◽

Sabine Willems ◽

Xiaomin Ni ◽

Jan Heering ◽

Apirat Chaikuad ◽

...

Keyword(s):

Drug Target ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Hepatocyte Nuclear Factor ◽

Structure Activity ◽

Starting Point ◽

Ligand Discovery ◽

Elevated Activity ◽

Hepatocyte Nuclear Factor 4Α ◽

Micromolar Range

Hepatocyte nuclear factor 4α (HNF4α) is a ligand-sensing transcription factor and presents as a potential drug target in metabolic diseases and cancer. In humans, mutations in the HNF4α gene cause maturity-onset diabetes of the young (MODY), and the elevated activity of this protein has been associated with gastrointestinal cancers. Despite the high therapeutic potential, available ligands and structure–activity relationship knowledge for this nuclear receptor are scarce. Here, we disclose a chemically diverse collection of orthogonally validated fragment-like activators as well as inverse agonists, which modulate HNF4α activity in a low micromolar range. These compounds demonstrate the druggability of HNF4α and thus provide a starting point for medicinal chemistry as well as an early tool for chemogenomics.

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Discovery of Antibacterial Agents Inhibiting the Energy-Coupling Factor (ECF) Transporters by Structure-Based Virtual Screening

10.26434/chemrxiv.11728710 ◽

2020 ◽

Author(s):

Eleonora Diamanti ◽

Inda Setyawati ◽

Spyridon Bousis ◽

leticia mojas ◽

lotteke Swier ◽

...

Keyword(s):

Virtual Screening ◽

Antibacterial Agents ◽

Antimicrobial Agents ◽

Energy Coupling ◽

Coupling Factor ◽

Design Synthesis ◽

Screening Design ◽

Starting Point ◽

Wide Range ◽

Vitamin Uptake

Here, we report on the virtual screening, design, synthesis and structure–activity relationships (SARs) of the first class of selective, antibacterial agents against the energy-coupling factor (ECF) transporters. The ECF transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. Because of their central role in the metabolism of bacteria and their absence in humans, ECF transporters are novel potential antimicrobial targets to tackle infection. The hit compound’s metabolic and plasma stability, the potency (20, MIC Streptococcus pneumoniae = 2 µg/mL), the absence of cytotoxicity and a lack of resistance development under the conditions tested here suggest that this scaffold may represent a promising starting point for the development of novel antimicrobial agents with an unprecedented mechanism of action.<br>

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A common mechanism links activities of butyrate in the colon

10.26434/chemrxiv.5414065.v1 ◽

2017 ◽

Author(s):

Mohit S. Verma ◽

Michael J. Fink ◽

Gabriel L Salmon ◽

Nadine Fornelos ◽

Takahiro E. Ohara ◽

...

Keyword(s):

Stem Cells ◽

Histone Deacetylases ◽

Biological Activities ◽

Short Chain Fatty Acids ◽

Common Mechanism ◽

Epithelial Stem Cells ◽

Degree Of Unsaturation ◽

Structure Activity ◽

Starting Point ◽

New Compounds

Two biological activities of butyrate in the colon (suppression of proliferation of colonic epithelial stem cells and inflammation) correlate with inhibition of histone deacetylases. Cellular and biochemical studies of molecules similar in structure to butyrate, but different in molecular details (functional groups, chain-length, deuteration, oxidation level, fluorination, or degree of unsaturation) demonstrated that these activities were sensitive to molecular structure, and were compatible with the hypothesis that butyrate acts by binding to the Zn<sup>2+</sup> in the catalytic site of histone deacetylases. Structure-activity relationships drawn from a set of 36 compounds offer a starting point for the design of new compounds targeting the inhibition of histone deacetylases. The observation that butyrate was more potent than other short-chain fatty acids is compatible with the hypothesis that crypts evolved (at least in part), to separate stem cells at the base of crypts from butyrate produced by commensal bacteria.

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Applications of Quantitative Structure-Activity Relationships (QSAR) based Virtual Screening in Drug Design: A Review

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200429102334 ◽

2020 ◽

Vol 20 (14) ◽

pp. 1375-1388 ◽

Cited By ~ 2

Author(s):

Patnala Ganga Raju Achary

Keyword(s):

Machine Learning ◽

Drug Discovery ◽

Virtual Screening ◽

Model Building ◽

Chemical Space ◽

Qsar Model ◽

Quantitative Structure ◽

Efficient Manner ◽

Qsar Analysis ◽

Structure Activity

The scientists, and the researchers around the globe generate tremendous amount of information everyday; for instance, so far more than 74 million molecules are registered in Chemical Abstract Services. According to a recent study, at present we have around 1060 molecules, which are classified as new drug-like molecules. The library of such molecules is now considered as ‘dark chemical space’ or ‘dark chemistry.’ Now, in order to explore such hidden molecules scientifically, a good number of live and updated databases (protein, cell, tissues, structure, drugs, etc.) are available today. The synchronization of the three different sciences: ‘genomics’, proteomics and ‘in-silico simulation’ will revolutionize the process of drug discovery. The screening of a sizable number of drugs like molecules is a challenge and it must be treated in an efficient manner. Virtual screening (VS) is an important computational tool in the drug discovery process; however, experimental verification of the drugs also equally important for the drug development process. The quantitative structure-activity relationship (QSAR) analysis is one of the machine learning technique, which is extensively used in VS techniques. QSAR is well-known for its high and fast throughput screening with a satisfactory hit rate. The QSAR model building involves (i) chemo-genomics data collection from a database or literature (ii) Calculation of right descriptors from molecular representation (iii) establishing a relationship (model) between biological activity and the selected descriptors (iv) application of QSAR model to predict the biological property for the molecules. All the hits obtained by the VS technique needs to be experimentally verified. The present mini-review highlights: the web-based machine learning tools, the role of QSAR in VS techniques, successful applications of QSAR based VS leading to the drug discovery and advantages and challenges of QSAR.

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Virtual Screening, Molecular Modelling and Biochemical Studies to Exploit PF14_0660 as a Target to Identify Novel Anti-malarials

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180727121200 ◽

2019 ◽

Vol 16 (4) ◽

pp. 417-426

Author(s):

Vimee Raturi ◽

Kumar Abhishek ◽

Subhashis Jana ◽

Subhendu Sekhar Bag ◽

Vishal Trivedi

Keyword(s):

Virtual Screening ◽

Phosphatase Activity ◽

Molecular Modelling ◽

Drug Target ◽

Antimalarial Activity ◽

Biochemical Study ◽

Tyrosine Phosphatase ◽

Host Protein ◽

Dependent Manner ◽

Multiple Sequence

Background: Malaria Parasite relies heavily on signal transduction pathways to control growth, the progression of the life cycle and sustaining stress for its survival. Unlike kinases, Plasmodium's phosphatome is one of the smallest and least explored for identifying drug target for clinical intervention. PF14_0660 is a putative protein present on the chromosome 14 of Plasmodium falciparum genome. Methods: Multiple sequence alignment of PF14_0660 with other known protein phosphatase indicate the presence of phosphatase motif with specific residues essential for metal binding, catalysis and providing structural stability. PF14_0660 is a mixed α/β type of protein with several β -sheet and α-helix arranged to form βαβαβα sub-structure. The surface properties of PF14_0660 is conserved with another phosphate of this family, but it profoundly diverges from the host protein tyrosine phosphatase. PF14_0660 was cloned, over-expressed and protein is exhibiting phosphatase activity in a dose-dependent manner. Docking of Heterocyclic compounds from chemical libraries into the PF14_0660 active site found nice fitting of several candidate molecules. Results: Compound PPinh6, PPinh 7 and PPinh 5 are exhibiting antimalarial activity with an IC50 of 1.4 ± 0.2µM, 3.8 ± 0.3 µM and 9.4 ± 0.6&#181M respectively. Compound PPinh 6 and PPinh 7 are inhibiting intracellular PF14_0660 phosphatase activity and killing parasite through the generation of reactive oxygen species. Conclusion: Hence, a combination of molecular modelling, virtual screening and biochemical study allowed us to explore the potentials of PF14_0660 as a drug target to design anti-malarials.

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Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

International Journal of Molecular Sciences ◽

10.3390/ijms22137236 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7236

Author(s):

Endah Dwi Hartuti ◽

Takaya Sakura ◽

Mohammed S. O. Tagod ◽

Eri Yoshida ◽

Xinying Wang ◽

...

Keyword(s):

Drug Target ◽

De Novo ◽

Dihydroorotate Dehydrogenase ◽

Chemical Library ◽

New Class ◽

De Novo Biosynthesis ◽

Starting Point ◽

Novel Drugs ◽

Low Toxicity ◽

Fourth Step

Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.

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Identification of Novel Cathepsin B Inhibitors with Implications in Alzheimer’s Disease: Computational Refining and Biochemical Evaluation

Cells ◽

10.3390/cells10081946 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1946

Author(s):

Nitin Chitranshi ◽

Ashutosh Kumar ◽

Samran Sheriff ◽

Veer Gupta ◽

Angela Godinez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hydrogen Bond ◽

Virtual Screening ◽

Cathepsin B ◽

Amyloid Β ◽

Proteolytic Degradation ◽

Hydrogen Bond Acceptor ◽

Starting Point ◽

The Brain

Amyloid precursor protein (APP), upon proteolytic degradation, forms aggregates of amyloid β (Aβ) and plaques in the brain, which are pathological hallmarks of Alzheimer’s disease (AD). Cathepsin B is a cysteine protease enzyme that catalyzes the proteolytic degradation of APP in the brain. Thus, cathepsin B inhibition is a crucial therapeutic aspect for the discovery of new anti-Alzheimer’s drugs. In this study, we have employed mixed-feature ligand-based virtual screening (LBVS) by integrating pharmacophore mapping, docking, and molecular dynamics to detect small, potent molecules that act as cathepsin B inhibitors. The LBVS model was generated by using hydrophobic (HY), hydrogen bond acceptor (HBA), and hydrogen bond donor (HBD) features, using a dataset of 24 known cathepsin B inhibitors of both natural and synthetic origins. A validated eight-feature pharmacophore hypothesis (Hypo III) was utilized to screen the Maybridge chemical database. The docking score, MM-PBSA, and MM-GBSA methodology was applied to prioritize the lead compounds as virtual screening hits. These compounds share a common amide scaffold, and showed important interactions with Gln23, Cys29, His110, His111, Glu122, His199, and Trp221. The identified inhibitors were further evaluated for cathepsin-B-inhibitory activity. Our study suggests that pyridine, acetamide, and benzohydrazide compounds could be used as a starting point for the development of novel therapeutics.

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Characterizing the structure–activity relationships of natural products, tanshinones, reveals their mode of action in inhibiting spleen tyrosine kinase

RSC Advances ◽

10.1039/d0ra08769f ◽

2021 ◽

Vol 11 (4) ◽

pp. 2453-2461

Author(s):

Min-Che Tung ◽

Keng-Chang Tsai ◽

Kit-Man Fung ◽

Ming-Jaw Don ◽

Tien-Sheng Tseng

Keyword(s):

Natural Products ◽

Protein Kinase ◽

Tyrosine Kinase ◽

Mode Of Action ◽

Drug Target ◽

Receptor Protein ◽

Inflammatory Disorder ◽

Spleen Tyrosine Kinase ◽

Structure Activity Relationships ◽

Structure Activity

The cytosolic non-receptor protein kinase, spleen tyrosine kinase (SYK), is an attractive drug target in autoimmune, inflammatory disorder, and cancers indications.

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Learning the Edit Costs of Graph Edit Distance Applied to Ligand-Based Virtual Screening

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200603122000 ◽

2020 ◽

Vol 20 (18) ◽

pp. 1582-1592 ◽

Cited By ~ 1

Author(s):

Carlos Garcia-Hernandez ◽

Alberto Fernández ◽

Francesc Serratosa

Keyword(s):

Virtual Screening ◽

Edit Distance ◽

Graph Matching ◽

Optimization Techniques ◽

Graph Edit Distance ◽

Structure Activity ◽

Future Drug ◽

Minimum Number ◽

Type Node ◽

Activity Information

Background: Graph edit distance is a methodology used to solve error-tolerant graph matching. This methodology estimates a distance between two graphs by determining the minimum number of modifications required to transform one graph into the other. These modifications, known as edit operations, have an edit cost associated that has to be determined depending on the problem. Objective: This study focuses on the use of optimization techniques in order to learn the edit costs used when comparing graphs by means of the graph edit distance. Methods: Graphs represent reduced structural representations of molecules using pharmacophore-type node descriptions to encode the relevant molecular properties. This reduction technique is known as extended reduced graphs. The screening and statistical tools available on the ligand-based virtual screening benchmarking platform and the RDKit were used. Results: In the experiments, the graph edit distance using learned costs performed better or equally good than using predefined costs. This is exemplified with six publicly available datasets: DUD-E, MUV, GLL&GDD, CAPST, NRLiSt BDB, and ULS-UDS. Conclusion: This study shows that the graph edit distance along with learned edit costs is useful to identify bioactivity similarities in a structurally diverse group of molecules. Furthermore, the target-specific edit costs might provide useful structure-activity information for future drug-design efforts.

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