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 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.                                                             

Identification of Selective Receptor Modulators Using Pharmacoinformatics Approaches for Therapeutic Application in Estrogen Therapy

2019 ◽  
Vol 4 (2) ◽  
pp. 52-81
Author(s):  
Md Ataul Islam ◽  
Shovonlal Bhowmick ◽  
Achintya Saha
Keyword(s):  
Hydrogen Bond ◽  
Estrogen Therapy ◽  
Docking Study ◽  
Hydrogen Bond Donor ◽  
Molecular Docking Study ◽  
Hydrogen Bond Acceptor ◽  
Validation Tests ◽  
Receptor Modulators ◽  
Analysis Of Binding Energy ◽  
Pharmacophore Models

Pharmacoinformatics strategies have been applied to explore promising selective estrogen receptor (ER) modulators (SERMs). A set of non-steroidal ligands was considered for both ERα and ERβ subtypes. Best pharmacophore models revealed with importance of hydrogen bond acceptor and hydrophobicity for both subtypes, along with an aromatic ring and hydrogen bond donor for α and β subtypes, respectively. Both models were validated, and further considered for virtual screening of National Cancer Institute database. Initial hits were sorted with a number of criteria, and finally the molecules have been proposed as promising SERMs. A molecular docking study explained that screened ligands formed a number of binding interactions with both ERs. The subtype receptors in complex with active and screened compounds were considered for molecular simulations to compare stability of the complexes. An analysis of binding energy found that screened ligands hold a strong affinity towards the selective receptor cavity. The proposed ligands might be promising leads for estrogen therapy after experimental validation tests.

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.

Pharmacophore-based screening for identification of Human Acyl-CoA cholesterol acyltransferase inhibitors: An in-silico study

2020 ◽  
Vol 18 ◽  
Author(s):  
Ankit Dhaundiyal ◽  
Puja Kumari ◽  
Shasta Kalra
Keyword(s):  
Hydrogen Bond ◽  
Cholesterol Acyltransferase ◽  
Three Dimensional ◽  
Pharmacophore Model ◽  
Fatty Acyl ◽  
Hydrogen Bond Donor ◽  
Data Set ◽  
Hydrogen Bond Acceptor ◽  
Discovery Studio ◽  
Acyltransferase Inhibitors

Abstract:: Human Acyl-CoA cholesterol acyltransferase (ACAT) plays an important role in catalysis of reaction which converts cholesterol into cholesteryl esters and long-chain fatty acyl coenzyme A. The inhibition of ACAT has therapeutically potential roles in hypercholestrolemia, atherosclerosis and coronary heart disease. For better understanding of essential chemical features for ACAT inhibition and identifying novel inhibitors, a three-dimensional (3D) chemical-feature-based quantitative QSAR pharmacophore model for available ACAT inhibitors have been developed for first time using Discovery Studio 2.5. The best model (Hypo1) having lowest total cost (84.14), highest cost difference (69.67), highest correlation coefficient (0.94), and lowest RMS (1.15Å), constitutes of one hydrogen bond acceptor, one hydrogen bond donor, two hydrophobic aromatic and one hydrophobic aliphatic feature. Validation of Hypo1 was further done using test set activity prediction, Fischer’s randomization method and decoy data set to check the reliability of the model. The validated Hypo1 was then used as a 3D search query for virtual screening to retrieve potential inhibitors from National cancer institute (NCI), ChemDiv and Specs databases. Finally, ADMET properties of selected compounds were calculated. The result shows the good potential of the newly found ACAT inhibitors. Finally, the two compounds have been obtained as novel hits to design the Novel ACAT inhibitors.

6,9-Dibromo-2a,10b-diphenyl-2a,5,10,10b-tetrahydro-2H,3H-2,3,4a,10a-tetraazabenzo[g]cyclopenta[cd]azulene-1,4-dione monohydrate

2006 ◽  
Vol 62 (5) ◽  
pp. o1754-o1755
Author(s):  
Neng-Fang She ◽  
Sheng-Li Hu ◽  
Hui-Zhen Guo ◽  
An-Xin Wu
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Water Molecule ◽  
Title Compound ◽  
Supramolecular Structure ◽  
Hydrogen Bond Donor ◽  
Hydrogen Bond Acceptor ◽  
Compound C ◽  
Bifurcated Hydrogen Bond

The title compound, C24H18Br2N4O2·H2O, forms a supramolecular structure via N—H...O, O—H...O and C—H...O hydrogen bonds. In the crystal structure, the water molecule serves as a bifurcated hydrogen-bond acceptor and as a hydrogen-bond donor.

scholarly journals Machine learning models for hydrogen bond donor and acceptor strengths using large and diverse training data generated by first-principles interaction free energies

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Christoph A. Bauer ◽  
Gisbert Schneider ◽  
Andreas H. Göller
Keyword(s):  
Machine Learning ◽  
Hydrogen Bond ◽  
Hydrogen Bonding ◽  
Training Data ◽  
Free Energies ◽  
Hydrogen Bond Donor ◽  
Chemical Application ◽  
Hydrogen Bond Acceptor ◽  
Donor And Acceptor ◽  
Target Values

Abstract We present machine learning (ML) models for hydrogen bond acceptor (HBA) and hydrogen bond donor (HBD) strengths. Quantum chemical (QC) free energies in solution for 1:1 hydrogen-bonded complex formation to the reference molecules 4-fluorophenol and acetone serve as our target values. Our acceptor and donor databases are the largest on record with 4426 and 1036 data points, respectively. After scanning over radial atomic descriptors and ML methods, our final trained HBA and HBD ML models achieve RMSEs of 3.8 kJ mol−1 (acceptors), and 2.3 kJ mol−1 (donors) on experimental test sets, respectively. This performance is comparable with previous models that are trained on experimental hydrogen bonding free energies, indicating that molecular QC data can serve as substitute for experiment. The potential ramifications thereof could lead to a full replacement of wetlab chemistry for HBA/HBD strength determination by QC. As a possible chemical application of our ML models, we highlight our predicted HBA and HBD strengths as possible descriptors in two case studies on trends in intramolecular hydrogen bonding.

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.

Infrared spectroscopic characterization of hydrogen-bonded propylene oxide − ethanol and propylene oxide − 2-fluoroethanol complexes isolated in solid neon matrices

2013 ◽  
Vol 91 (12) ◽  
pp. 1292-1302 ◽  
Author(s):  
Osama Y. Ali ◽  
Elyse Jewer ◽  
Travis D. Fridgen
Keyword(s):  
Hydrogen Bond ◽  
Propylene Oxide ◽  
Spectroscopic Characterization ◽  
Hydrogen Bond Donor ◽  
Hydrogen Bond Acceptor ◽  
Reduced Frequency ◽  
Enthalpy Of Proton Transfer ◽  
The Difference ◽  
Bonded Complexes ◽  
Hydrogen Bonded

The infrared absorption spectra of hydrogen-bonded complexes of propylene oxide with either ethanol or 2-fluoroethanol have been recorded in neon matrices. Mixtures of propylene oxide and ethanol or propylene oxide and 2-fluoroethanol vapors were mixed with an excess of neon gas and deposited onto a KBr substrate at 4.2 K. The results indicate that hydrogen-bonded complexes were formed with propylene oxide as the hydrogen bond acceptor and either ethanol or 2-fluoroethanol as the hydrogen bond donors. The features assigned to the O−H stretch were red-shifted by 175 and 193 cm−1 for the ethanol- and 2-fluoroethanol-containing complexes, respectively. The difference in red shifts can be accounted for due to the greater acidity of 2-fluroethanol. Deuterium isotope experiments were conducted to help confirm the assignment of the O–H stretch for the complexes. As well, structures and infrared spectra were calculated using B3LYP/6-311++G(2d,2p) calculations and were used to compare with the experimental spectra. A “scaling equation” rather than a scaling factor was used and is shown to greatly increase the utility of the calculations when comparing with experimental spectra. An examination of the O–H stretching red shifts for many hydrogen-bound complexes reveals a relationship between the shift and the difference between the acidity of the hydrogen bond donor and the basicity of the hydrogen bond acceptor (the enthalpy of proton transfer). Both hydrogen-bonded complexes and proton-bound complexes appear to have a maximum in the reduced frequency value that corresponds to complexes where the hydrogen/proton are equally shared between the two bases.

Enthalpies of interaction of nitrogen base solutes with organic solvents

1985 ◽  
Vol 63 (9) ◽  
pp. 2540-2544 ◽  
Author(s):  
W. Kirk Stephenson ◽  
Richard Fuchs
Keyword(s):  
Hydrogen Bond ◽  
Organic Solvents ◽  
Butyl Alcohol ◽  
Hydrogen Bond Donor ◽  
Butyl Ether ◽  
Hydrogen Bond Acceptor ◽  
Nitrogen Base ◽  
Benzene Toluene ◽  
Polar Interactions ◽  
S Model

Heats of solution of triethylamine, aniline, pyridine, and model compounds (3-ethylpentane, benzene) in 17 organic solvents (n-heptane, cyclohexane, carbon tetrachloride, 1,2-dichloroethane, α,α,α-trifluorotoluene, triethylamine, butyl ether, ethyl acetate, dimethylformamide, dimethyl sulfoxide, benzene, toluene, mesitylene, t-butyl alcohol, 1-octanol, methanol, 2,2,2-trifluoroethanol) have been combined with solute heats of vaporization to give enthalpies of transfer from vapor to solvent (ΔH(v → s)). Differences between solute and model values (ΔΔH(v → s) = ΔH(v → s) (solute) – ΔH(v → s) (model)) were used to evaluate nitrogen base solute–solvent polar interactions. Correlations of ΔΔH(v → s) with Taft–Kamlet solvatochromic parameters (π*, α, β) have been determined.Aniline was found to be a better hydrogen bond donor acid than hydrogen bond acceptor base. Nevertheless, alcohols donate H-bonds to aniline. Triethylamine and pyridine are stronger HBA bases than aniline. The π* (dipolarity–polarizability) parameter of aniline (as a solute) is calculated to be 1.10.

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