scholarly journals The Exploration of Novel Pharmacophore Characteristics and Multidirectional Elucidation of Structure-Activity Relationship and Mechanism of Sesquiterpene Pyridine Alkaloids from Tripterygium Based on Computational Approaches

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Chengyan Long ◽  
Yang Yang ◽  
Yong Yang ◽  
Sixing Huang ◽  
Xiaomei Zhang ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Nicotinic Acid ◽  
Pyridine Ring ◽  
Cannabinoid Receptor ◽  
Pharmacophore Model ◽  
Structural Difference ◽  
Cannabinoid Receptor 1 ◽  
Hydrogen Bond Acceptor ◽  
Pharmacologically Active ◽  
Sesquiterpene Pyridine Alkaloids

Sesquiterpene pyridine alkaloids are a large group of highly oxygenated sesquiterpenoids, which are characterized by a macrocyclic dilactone skeleton containing 2-(carboxyalkyl) nicotinic acid and dihydro-β-agarofuran sesquiterpenoid, and are believed to be the active and less toxic components of Tripterygium. In this study, 55 sesquiterpene pyridine alkaloids from Tripterygium were subjected to identification of pharmacophore characteristics and potential targets analysis. Our results revealed that the greatest structural difference of these compounds was in the pyridine ring and the pharmacophore model-5 (Pm-05) was the best model that consisted of three features including hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), and hydrophobic (HY), especially hydrophobic group located in the pyridine ring. It was proposed that 2-(carboxyalkyl) nicotinic acid part possessing a pyridine ring system was not only a pharmacologically active center but also a core of structural diversity of alkaloids from Tripterygium wilfordii. Furthermore, sesquiterpene pyridine alkaloids from Tripterygium were predicted to target multiple proteins and pathways and possibly played essential roles in the cure of Alzheimer’s disease, breast cancer, Chagas disease, and nonalcoholic fatty liver disease (NAFLD). They also had other pharmacological effects, depending on the binding interactions between pyridine rings of these compounds and active cavities of the target genes platelet-activating factor receptor (PTAFR), cannabinoid receptor 1 (CNR1), cannabinoid receptor 1 (CNR2), squalene synthase (FDFT1), and heat shock protein HSP 90-alpha (HSP90AA1). Taken together, the results of this present study indicated that sesquiterpene pyridine alkaloids from Tripterygium are promising candidates that exhibit potential for development as medicine sources and need to be promoted.

scholarly journals DESIGN AND SYNTHESIS OF SOME NEWER IMIDAZOLYL HETEROCYCLES AS POTENT BTK INHIBITORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS

2017 ◽  
Vol 9 (3) ◽  
pp. 80
Author(s):  
R. Priyadarsini ◽  
Anandhan Menaka
Keyword(s):  
Rheumatoid Arthritis ◽  
Hydrogen Bond ◽  
Molecular Docking ◽  
Tyrosine Kinase ◽  
Pharmacophore Model ◽  
Spectral Studies ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Hydrogen Bond Acceptor ◽  
Btk Inhibitors

Objective: The rheumatoid arthritis as a global health problem over the past few decades, Emphasizes the need for discovery of new therapeutic disease modifying anti-rheumatoid Arthritis drugs (DMARD’s). Bruton’s tyrosine kinase (BTK) is a cytoplasmic, non-receptor, tyrosine kinase which is expressed in most of the hematopoietic cells and plays an important role in the development, differentiation and proliferation of B-lineage cells, thus making BTK an efficient therapeutic target for the treatment of rheumatoid arthritis. This prompted us to synthesise a novel series of Imidazolyl Heterocycles as potent BTK (Bruton’s Tyrosine Kinase) inhibitors with alleged Anti-Rheumatoid Arthritis properties. Methods: Newer BTK inhibitors containing one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) and three hydrophobic features based on that pharmacophore model for BTK were designed. The designed compounds were sorted by applying ADMET properties, Lipinski rule of five, molecular docking and Novelty prediction to refine the designed ligands. Finally, different five compounds containing Imidazole as the heterocyclic nucleus have been synthesized and characterized by different analytical methods like Chromatographic data, Elemental analysis and Spectral studies by IR, 1H NMR, 13C NMR, GC-MS. Molecular docking studies were performed against BTK using GLIDE 10.2. Results: Several important hydrogen bonds with BTK were revealed, which include the gatekeeper residue Glu475 and Met477 at the hinge region. Conclusion: Overall, this study suggests that the proposed ligands are found to be more effective BTK inhibitor as Anti-Rheumatoid arthritis agents.

scholarly journals The Characteristics of PD-L1 Inhibitors, from Peptides to Small Molecules

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1940 ◽  
Author(s):  
Yanwen Zhong ◽  
Xuanyi Li ◽  
Hequan Yao ◽  
Kejiang Lin
Keyword(s):  
Hydrogen Bond ◽  
Small Molecules ◽  
Pharmacophore Model ◽  
Amino Acid Residues ◽  
Tumor Treatment ◽  
Hydrogen Bond Donor ◽  
Treatment Results ◽  
Hydrogen Bond Acceptor ◽  
Checkpoint Pathway ◽  
Pharmacophore Models

The programmed cell death ligand protein 1 (PD-L1) is a member of the B7 protein family and consists of 290 amino acid residues. The blockade of the PD-1/PD-L1 immune checkpoint pathway is effective in tumor treatment. Results: Two pharmacophore models were generated based on peptides and small molecules. Hypo 1A consists of one hydrogen bond donor, one hydrogen bond acceptor, two hydrophobic points and one aromatic ring point. Hypo 1B consists of one hydrogen bond donor, three hydrophobic points and one positive ionizable point. Conclusions: The pharmacophore model consisting of a hydrogen bond donor, hydrophobic points and a positive ionizable point may be helpful for designing small-molecule inhibitors targeting PD-L1.

Sub-Pharmacophore Generation of JNK3 Inhibitors

2013 ◽  
Vol 444-445 ◽  
pp. 1756-1760 ◽  
Author(s):  
Yan Ling Zhang ◽  
Yuan Ming Wang ◽  
Yan Jiang Qiao
Keyword(s):  
Hydrogen Bond ◽  
Pharmacophore Model ◽  
High Specificity ◽  
Data Bank ◽  
Chinese Herbs ◽  
Mitogen Activated Protein Kinase ◽  
Specific Class ◽  
Hydrogen Bond Donor ◽  
Hydrogen Bond Acceptor ◽  
Appraisal Index

The structure-based pharmacophore (SBP) model is consisted by the complementarity of the chemical features and space of the interaction between the ligand and receptor. The SBP models always have a high specificity which can only represent the specific class of the ligand. To simplify the models, sub-pharmacophore was then proposed in present study, and was expected to have and only have the most important or the common chemical features which play the major role in the interaction of ligand and receptor. Sub-pharmacophore should contain 4-6 features, the higher specificity with more features, and vice versa. The sub-pharmacophore was generated by the random combination of features from the structure-based models. With the MDL Drug Data Report database used as the testing database, a new metric CAI (comprehensive appraisal index), which integrated the metrics of E and A%, was defined and used to determine the best sub-pharmacophore model. C-Jun N-terminal kinase (JNKs) is one of the mitogen-activated protein kinase family, and widely involved in immune response and inflammatory response, and other pathological processes. JNK3 is mainly distributed in the brain and nervous system. In present study, twenty-five initial SBP models of JNK3 inhibitors were directly constructed from the Protein Data Bank (PDB) complexes by the LigandScout software. Then, 1018 sub-pharmacophore models were obtained from the 25 initial models. Finally, the best sub-pharmacophore was determined which was simplified from the initial model generated from the 3FI2 complex, and included four features: one hydrogen bond donor, one hydrogen bond acceptor, and two hydrophobic groups. The metrics of E, A% and CAI value of the best sub-pharmacophore model are 17.47, 31.15 and 5.44, respectively. The potential JNK3 inhibitors were then identified from Chinese herbs with the best sub-pharmacophore model, and 286 compounds were obtained.

scholarly journals Antimalarial phytochemicals as inhibitors against COVID-19 ACE2 receptor: Computational screening

2021 ◽  
Vol 13 (2) ◽  
pp. 10835
Author(s):  
Ouided BENSLAMA ◽  
Nedjwa MANSOURI ◽  
Rabah ARHAB
Keyword(s):  
Hydrogen Bond ◽  
In Silico ◽  
Pharmacophore Model ◽  
In Silico Analysis ◽  
Active Site Residues ◽  
Hydrophobic Region ◽  
Hydrogen Bond Acceptor ◽  
Computational Screening ◽  
Docking Approach ◽  
Therapeutic Molecules

Quinine, artemisinin, febrifugine, brusatol, chaparrin tehranolide, glaucarubin, sergeoliden, and yingzhaosu A, nine antimalarial phytochemicals, were the focus of an in-silico analysis aimed at discovering new therapeutic molecules against COVID-19 infection. The screening of these molecules included a molecular docking approach within the Angiotensin-converting enzyme-2 (ACE2) receptor. In addition, drug-likeness, ADMET analysis and pharmacophore mapping have been performed. The result of the docking process was based on the energy binding values as well as the number and type of interactions established with the receptor active site residues, which were compared with those of co-crystallized ligand and chloroquine. Febrifugine showed the most interesting energetic and interactive activities that were closer to the reference molecule and better than those of chloroquine. Whereas artemisinin has produced results that are the closest to those of chloroquine. Similarly, drug-likeness and ADMET analysis have shown that febrifugine and artemisinin check most of the filters and pharmacokinetic properties required for the choice of an effective therapeutic molecule. A pharmacophore model was designed on the basis of a training set consisting of the most relevant molecules; it has one metal ligator cum hydrophobic region cum hydrogen bond acceptor, one hydrogen bond acceptor cum metal ligator and one hydrophobic aromatic ring. This model is proposed to be used for the in-silico discovery of new therapeutic molecules against coronavirus.

scholarly journals IDENTIFICATION OF POTENTIAL INHIBITORS FOR LOWERING CHOLESTEROL LEVEL BY INHIBITING PCSK9

2016 ◽  
Vol 9 (6) ◽  
pp. 230 ◽  
Author(s):  
Rathi Suganya
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Cholesterol Level ◽  
Ldl Cholesterol ◽  
Ldl Receptor ◽  
Pharmacophore Model ◽  
Dynamics Simulation ◽  
Hydrogen Bond Donor ◽  
Hydrogen Bond Acceptor ◽  
Cholesterol Levels

ABSTRACTObjective: PCSK9 has medical significance in lowering cholesterol levels. Inhibitors target and inactivate PCSK9 in the liver. Knocking out PCSK9 (proprotein convertase subtilisin kexin 9) reduces the amount of harmful LDL cholesterol circulating in the bloodstream. There are two known inhibitors for treating the cardiovascular disease “Arilocumab” and “Evalocumab”. However there are many side-effects. The current study is to identify natural and synthetic inhibitor using the pharmacophoric feature of the known inhibitor and validating the short listed candidates using Molecular dynamics and ADMET properties.Methods: Known inhibitors for the PCSK9 Protein were taken from the BINDING DATABASE. Molecular docking was performed for the known inhibitors with the PCSK9 protein. After docking the best inhibitor was selected and the docking result was then imported to find the pharmacophoric features.Results: The pharmacophore model was generated with 3 features containing  1 hydrogen bond acceptor(A),1 Hydrogen bond donor(B) and 1 Aromatic ring. The constructed e-pharmacophore model was screened with more than 20000 natural compounds. 5 compounds were short listed. Among them ZINC85625485 has  glide  score  of  -13.03  kcal/mol  with  glide  energy  was  -57.62 kcal/mol and ZINC85625406 has glide score of -8.1kcal/mol with glide energy was -39.33kcal/mol were taken as the best Hits.Conclusion: PCSK9 is known to be a therapeutic agent as it controls the plasma LDL cholesterol levels by posttranslational regulation of the LDL receptor. Therefore, up-regulation of PCSk9 can lead to elevated cholesterol level in such case inhibition of PCSK9 will be a effective remedy. In this study already known inhibitors were taken and pharmacophore feature was generated. Zinc database was screened to find out novel compounds with similar pharmacophore features that can act as potentially active compound against PCSK9. ZINC85625485 and ZINC85625406 were short listed as lead compounds with Molecular dynamics simulation and checking the ADMET properties. Keywords: PCSK9, Docking, ADMET, Molecular Dynamics.                                                             

scholarly journals Structure-activity relationship study of steroidal 1,2,4,5-tetraoxane animalarials using computational procedures

2005 ◽  
Vol 70 (3) ◽  
pp. 329-345 ◽  
Author(s):  
Apurba Bhattacharjee ◽  
Keith Carvalho ◽  
Dejan Opsenica ◽  
Bogdan Solaja
Keyword(s):  
Hydrogen Bond ◽  
Antimalarial Activity ◽  
Three Dimensional ◽  
Pharmacophore Model ◽  
Plasmodium Falciparum Malaria ◽  
Multidrug Resistant ◽  
Heme Iron ◽  
Hydrogen Bond Acceptor ◽  
Computational Procedures

A three-dimensional QSAR pharmacophore model for antimalarial activity of steroidal 1,2,4,5-tetraoxanes was developed from a set of 17 substituted antimalarial derivatives out of 27 analogues that exhibited remarkable in vitro activity (below 100 ng/mL) against sensitive and multidrug-resistant Plasmodium falciparum malaria. The pharmacophore, which contains two hydrogen bond acceptors (lipid) and one hydrophobic (aliphatic) feature, was found to map well onto the potent analogues and many other well-known antimalarial trioxane drugs including artemisinin, arteether, artesunic acid, and tetraoxanes. The presence of at least one hydrogen bond acceptor in the trioxane or the tetraoxane moiety appears to be necessary for potent activity of this class of compounds. Docking calculations of some of these compounds with heme are consistent with the above observation as the proximity of the heme iron to the oxygen atom of the trioxane or the tetraoxane moiety favors potent activity of the compounds. Electron transfer from the oxygen of trioxane or the tetraoxane appears to be crucial for mechanism of action of the compounds. This information together with the pharmacophore should enable search for new peroxide containing antimalarial candidates from databases and custom designed synthesis of more efficacious and safer analogues.

scholarly journals Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP3R) Inhibitors in Cancer

2021 ◽  
Vol 22 (23) ◽  
pp. 12993
Author(s):  
Humaira Ismatullah ◽  
Ishrat Jabeen
Keyword(s):  
Hydrogen Bond ◽  
Cancer Progression ◽  
Molecular Descriptor ◽  
Pharmacophore Model ◽  
Receptor Site ◽  
Structural Features ◽  
Hydrogen Bond Donor ◽  
Hydrogen Bond Acceptor ◽  
Design And Optimization ◽  
Trisphosphate Receptor

Inositol 1, 4, 5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling plays a pivotal role in different cellular processes, including cell proliferation and cell death. Remodeling Ca2+ signals by targeting the downstream effectors is considered an important hallmark in cancer progression. Despite recent structural analyses, no binding hypothesis for antagonists within the IP3-binding core (IBC) has been proposed yet. Therefore, to elucidate the 3D structural features of IP3R modulators, we used combined pharmacoinformatic approaches, including ligand-based pharmacophore models and grid-independent molecular descriptor (GRIND)-based models. Our pharmacophore model illuminates the existence of two hydrogen-bond acceptors (2.62 Å and 4.79 Å) and two hydrogen-bond donors (5.56 Å and 7.68 Å), respectively, from a hydrophobic group within the chemical scaffold, which may enhance the liability (IC50) of a compound for IP3R inhibition. Moreover, our GRIND model (PLS: Q2 = 0.70 and R2 = 0.72) further strengthens the identified pharmacophore features of IP3R modulators by probing the presence of complementary hydrogen-bond donor and hydrogen-bond acceptor hotspots at a distance of 7.6–8.0 Å and 6.8–7.2 Å, respectively, from a hydrophobic hotspot at the virtual receptor site (VRS). The identified 3D structural features of IP3R modulators were used to screen (virtual screening) 735,735 compounds from the ChemBridge database, 265,242 compounds from the National Cancer Institute (NCI) database, and 885 natural compounds from the ZINC database. After the application of filters, four compounds from ChemBridge, one compound from ZINC, and three compounds from NCI were shortlisted as potential hits (antagonists) against IP3R. The identified hits could further assist in the design and optimization of lead structures for the targeting and remodeling of Ca2+ signals in cancer.

Multifunctional arylsulfonamide derivatives with 5-HT6/5-HT7 receptor antagonistic activity: a structural study

2018 ◽  
Vol 74 (11) ◽  
pp. 1477-1486
Author(s):  
Justyna Kalinowska-Tłuścik ◽  
Agata Piaskowska ◽  
Marcin Kołaczkowski
Keyword(s):  
Hydrogen Bond ◽  
Functional Groups ◽  
Serotonin Receptor ◽  
Psychological Symptoms ◽  
Pharmacophore Model ◽  
Antagonistic Activity ◽  
Receptor Subtypes ◽  
Hydrogen Bond Acceptor ◽  
Number Of Patients ◽  
A Charge

Nowadays, a search for antagonists co-acting on serotonin receptor subtypes 6 and 7 (5-HT6R and 5-HT7R, respectively) is of great interest due to the increasing number of patients suffering from dementia and related behavioural and psychological symptoms. The X-ray crystal structures of four promising multifunctional ligands in the hydrochloride forms were determined, namely 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[3-(3-methylbenzenesulfonamido)propyl]piperidin-1-ium chloride, C22H27FN3O3S+·Cl−, (I), 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamido)butyl]piperidin-1-ium chloride, C25H28F2N3O3S2 +·Cl−, (II), 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[4-(6-fluorobenzo[b]thiophene-2-sulfonamido)butyl]piperidin-1-ium chloride, C24H26ClFN3O3S2 +·Cl−, (III), and 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[3-(3-chloro-4-fluorobenzenesulfonamido)propyl]piperidin-1-ium chloride, C21H22ClF2N3O3S2 +·Cl−, (IV). Two pharmacologically important functional groups, i.e. arylsulfonamide and piperidinyl–fluorobenzisoxazole, are linked by three- and four-membered aliphatic chains. These compounds crystallize as hydrochloride salts in monoclinic space groups, i.e. C2/c for (I), P21/c for (II) and (III), and P21/n for (IV). In the asymmetric unit, a charge-assisted hydrogen bond is observed between the cation located at the piperidine N atom and the chloride anion. The protonated piperidine N atom is critical to the pharmacological activity for the compounds, allowing for a strong interaction with monoaminergic receptors in the central nervous system. The sulfonyl group plays the role of a hydrogen-bond acceptor in the pharmacophore model and is involved in several C—H...O interactions. Two aromatic fragments of the presented structures are involved in C—H...π contacts, which were studied by Hirshfeld structure analysis. The distances between the mentioned functional groups are in agreement with pharmacophore models given in the literature. The studied interactions observed in the crystal structure indicate the main forces responsible for ligand–receptor recognition and binding.

scholarly journals Prediction of Novel Anoctamin1 (ANO1) Inhibitors Using 3D-QSAR Pharmacophore Modeling and Molecular Docking

2018 ◽  
Vol 19 (10) ◽  
pp. 3204 ◽  
Author(s):  
Yoon Lee ◽  
Gwan-Su Yi
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Correlation Coefficient ◽  
High Throughput Screening ◽  
Interaction Analysis ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Pharmacophore Modeling ◽  
Hydrogen Bond Acceptor ◽  
Test Set

Recently, anoctamin1 (ANO1), a calcium-activated chloride channel, has been considered an important drug target, due to its involvement in various physiological functions, as well as its possibility for treatment of cancer, pain, diarrhea, hypertension, and asthma. Although several ANO1 inhibitors have been discovered by high-throughput screening, a discovery of new ANO1 inhibitors is still in the early phase, in terms of their potency and specificity. Moreover, there is no computational model to be able to identify a novel lead candidate of ANO1 inhibitor. Therefore, three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore modeling approach was employed for identifying the essential chemical features to be required in the inhibition of ANO1. The pharmacophore hypothesis 2 (Hypo2) was selected as the best model based on the highest correlation coefficient of prediction on the test set (0.909). Hypo2 comprised a hydrogen bond acceptor, a hydrogen bond donor, a hydrophobic, and a ring aromatic feature with good statistics of the total cost (73.604), the correlation coefficient of the training set (0.969), and the root-mean-square deviation (RMSD) value (0.946). Hypo2 was well assessed by the test set, Fischer randomization, and leave-one-out methods. Virtual screening of the ZINC database with Hypo2 retrieved the 580 drug-like candidates with good potency and ADMET properties. Finally, two compounds were selected as novel lead candidates of ANO1 inhibitor, based on the molecular docking score and the interaction analysis. In this study, the best pharmacophore model, Hypo2, with notable predictive ability was successfully generated, and two potential leads of ANO1 inhibitors were identified. We believe that these compounds and the 3D-QSAR pharmacophore model could contribute to discovering novel and potent ANO1 inhibitors in the future.

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