QSAR AND PHARMACOPHORE MODELING OF 4-ARYLTHIENO [3, 2-d] PYRIMIDINE DERIVATIVES AGAINST ADENOSINE RECEPTOR OF PARKINSON'S DISEASE

2010 ◽  
Vol 09 (06) ◽  
pp. 975-991 ◽  
Author(s):  
SHIEK S. S. J. AHMED ◽  
A. AHAMEETHUNISA ◽  
WINKINS SANTOSH
Keyword(s):  
Structural Parameters ◽  
Pharmacophore Model ◽  
Structural Features ◽  
Pharmacophore Modeling ◽  
Hydrogen Bond Donor ◽  
Pyrimidine Derivatives ◽  
Antagonist Activity ◽  
Qsar Studies ◽  
Adenosine A1 ◽  
Adenosine A2a

A series of 47, 4-arylthieno[3, 2-d] pyrimidine derivatives was subjected to quantitative structure-antiparkinson activity relationships (QSAR) studies to evaluate the antagonist activity towards both adenosine A1 and adenosine A2A targets in Parkinson's drug discovery. QSAR models were derived with the aid of genetic function approximation (GFA) technique using descriptors to make connections between structural parameters and antiparkinson's activity followed by ADMET analysis and pharmacophore model generation. QSAR model was assessed using a test set of 12 compounds for A1 (r2 pred = 0.961), (q2 = 0.912) and 12 compounds for A2a (r2 pred = 0.914), (q2 = 0.781) receptor. The results revealed the significant role of DIPOLE MAG, CHI-V-3-P, WIENER, AREA, SC-2 and PHI-MAG descriptors in the antiparkinson activity of the studied compounds against adenosine A1 and adenosine A2A receptors. Subsequent, ADMET analysis shows 28 compounds can be the better candidates of drug and execution of pharmacophore model, explores the hydrogen bond donor, aromatic ring and hydrophobic groups are the key structural features for the antagonist activity.

Pharmacophore modeling and 3D-QSAR studies of 2,4-disubstituted pyrimidine derivatives as Janus kinase 3 inhibitors

2020 ◽  
Vol 19 (01) ◽  
pp. 2050001
Author(s):  
Neetu Agrawal
Keyword(s):  
Statistical Significance ◽  
Three Dimensional ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Pharmacophore Modeling ◽  
Janus Kinase ◽  
Hydrogen Bond Donor ◽  
Pyrimidine Derivatives ◽  
Qsar Studies ◽  
Janus Kinase 3

A robust pharmacophore model was developed and the structure-activity relationship was analyzed using 71 pyrimidine derivatives reported for covalent Janus Kinase 3 (JAK3) inhibition. Pharmacophore modeling developed a five featured pharmacophore: one H-bond acceptor, two H-bond donors, one hydrophobic, and one aromatic ring features. The atom-based three-dimensional QSAR models with statistical significance were generated using the training set of 52 compounds. The excellent predictive correlation coefficients were obtained for 3D models determined using a test set of 19 molecules. The generated QSAR model implies that the hydrophobic character is important for the JAK3 inhibitory activity of these compounds. Additionally, electron-withdrawing and hydrogen bond donor groups at specific positions positively contribute to the JAK3 inhibition potency. These results provided essential three-dimensional structural requirements and the crucial binding features of 2,4-disubstituted pyrimidine derivatives, which may direct for the design and discovery of novel potent JAK3 inhibitors.

scholarly journals STRUCTURE-ACTIVITY RELATIONSHIP: STUDY OF LEI-401 AS INHIBITOR OF NAPE-PLD BY PHARMACOPHORE MODEL

2021 ◽  
Vol 9 (5) ◽  
pp. 662-666
Author(s):  
Nilesh S. Kadu ◽  
Keyword(s):  
Metabolic Syndrome ◽  
Biological Activity ◽  
Phospholipase D ◽  
Pharmacophore Model ◽  
Structural Features ◽  
Pharmacophore Modeling ◽  
Physiological Processes ◽  
Structure Activity ◽  
Relationship Study

N-acyl-phosphatidylethanolamine phospholipase D (NAPE–PLD) is considered to be the principal enzyme that produces N-acylethanolamines (NAEs), a family of signaling lipids. NAEs are involved in numerous physiological processes such as appetite, satiety, pain, inflammation, fertility, stress, and anxiety. Furthermore, aberrant NAE levels are associated with metabolic syndrome and non-alcoholic steatohepatitis (NASH). Several inhibitors for NAPE–PLD have been reported. But most of the inhibitors showed poor to moderate potency for NAPE–PLD in vitro. Recently, Mario van der Stelt et al describe the SAR of NAPE–PLD inhibitors that afforded LEI–401 in vitro. However, no attempt was instigated to produce a consensus pharmacophore model of LEI–401 as inhibitors of NAPE–PLD. Pharmacophore modeling is an efficient and useful approach to identify important patterns in a series of molecules for optimizations. The consensus pharmacophore model revealed the importance of structural features and their correlation with the biological activity.

Novel 1,3,4-Triaryl Pyrazoles: Synthesis, QSAR Studies and Cytotoxicity against Breast Cancer

2019 ◽  
Vol 19 (7) ◽  
pp. 948-959 ◽  
Author(s):  
Magda M.F. Ismail ◽  
Amel M. Farrag ◽  
Marwa F. Harras
Keyword(s):  
Cell Cycle ◽  
Cytotoxic Activity ◽  
Flow Cytometric Analysis ◽  
Structural Features ◽  
Pharmacophore Modeling ◽  
Cytotoxic Agents ◽  
Pyrazole Derivatives ◽  
Mcf7 Cells ◽  
Qsar Studies ◽  
Induction Of Apoptosis

Background:The existence of drug-resistance and lack of selectivity encourages scientists to search for novel and more selective cytotoxic agents.Objective:In this work, novel 1,3,4-triarylpyrazole derivatives were synthesized to study their cytotoxicity on MCF7 (human breast Cell Line). In addition, QSAR studies were performed to show the relation between the cytotoxic activity and the structural features of our new synthesized pyrazole derivatives.Methods:Pyrazole-4-carbaldehyde derivative 3 was utilized as a starting material for the preparation of the new pyarazole derivatives. These target compounds were screened for their cytotoxic activity against MCF-7 followed by study cell cycle of the most active compounds. Finally, pharmacophore modeling and QSAR Studies was carried out.Results:Among these compounds; 5d and 8b showed the highest anti-proliferative activity (IC50 = 4.9 and 2.11 µM, respectively). Flow cytometric analysis showed that, compounds 5d and 8b arrested the cell cycle in addition to induction of apoptosis in MCF7 cells. Moreover, their stimulation effect on caspases 3/7 was examined to explore their mechanism of induction of apoptosis and the results showed that their proapoptotic activity could be due to the activation of caspases 3/7.Conclusion:Pyrazole derivatives 5d and 8b displayed potent bioactivities, indicating that these compounds could be considered as a new lead for more investigation in the future

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.

scholarly journals Study of Additional Interactions of Heterodimeric GW7604 Derivatives at the Coactivator Binding Site through Pharmacophore Modeling

2021 ◽  
Vol 9 (VI) ◽  
pp. 214-216
Author(s):  
Nilesh S. Kadu
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Binding Site ◽  
Clinical Stage ◽  
Endocrine Resistance ◽  
Pharmacophore Model ◽  
Structural Features ◽  
Pharmacophore Modeling ◽  
Binding Activity ◽  
Estrogen Receptor Modulators

Breast cancer is still the most common cancer in women worldwide, affecting one in eight women in high-income countries, and the incidence is further increasing. Endocrine therapy, including aromatase inhibitors or selective estrogen receptor modulators (SERMs)/selective estrogen receptor down-regulators (SERDs), consequently represents an indispensable treatment opportunity. Unfortunately, acquired endocrine resistance is an inevitable issue, which manifests after prolonged therapy. Consequently, developing a novel drug for the treatment of breast cancer is need of the hour. But it is an established fact that designing or repurposing a drug using ‘trial and error’ approach is a tricky, long, expensive and could be a failure in clinical stage. Hence, there is a need to employ alternative approaches like computer aided drug design (CADD) to overcome these shortcomings of conventional approach. Recently, CADD has gained a high popularity among drug designers and medicinal chemists due to several advances associated with it. Pharmacophore modeling is an efficient and useful approach to identify important patterns in a series of molecules for optimizations. Hence, in this analysis, an attempt is made to develop consensus pharmacophore model of heterodimeric GW7604 derivatives using alignment approach. The dataset consists of fourteen heterodimeric GW7604 derivatives exhibiting the binding activity in a transactivation assay ERα and ERβ to the coactivator binding site. The heterodimeric GW7604 derivatives possess good variation in substation pattern like the presence of different diaminoalkane spacer and CABS binder. The consensus pharmacophore model revealed the importance of structural features and their correlation with the biological activity.

Structural Investigations of Aroylindole Derivatives through 3D-QSAR and Multiple Pharmacophore Modeling for the Search of Novel Colchicines Inhibitor

2020 ◽  
Vol 17 ◽  
Author(s):  
Vijay K. Patel ◽  
Harish Rajak
Keyword(s):  
Virtual Screening ◽  
Anticancer Agents ◽  
Structural Alignment ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Qsar Model ◽  
Structural Features ◽  
Pharmacophore Modeling ◽  
Structural Investigations ◽  
Pharmacophore Modelling

Background : The ligand and structure based integrated strategies are being repeatedly and effectively employed for the precise search and design of novel ligands against various disease targets. Aroylindole derivative have a similar structural analogy as Combretastatin A-4, and exhibited potent anticancer activity on several cancer cell lines. Objective: To identify structural features of aroylindole derivatives through 3D-QSAR and multiple pharmacophore modelling for the search of novel colchicines inhibitor via virtual screening. Method: The present study utilizes ligand and structure based methodology for the establishment of structure activity correlation among trimethoxyaroylindole derivatives and search of novel colchicines inhibitor via virtual screening. The 3DQSAR studies were performed using Phase module and provided details of relationship between structure and biological activity. A single ligand based pharmacophore model was generated from Phase on compound 3 and compound 29 and three energetically optimized structure based pharmacophore models were generated from e-pharmacophore for co-crystallized ligand, compound 3 and compound 29 with protein PBD ID 1SA0, 5EYP and 5LYJ. These pharmacophoric features containing hit-like compounds were collected from commercially available ZINC database and screened using virtual screening workflow. Results and Discussion: The 3D-QSAR model studies with good PLSs statistics for factor four was characterized by the best prediction coefficient Q2 (0.8122), regression R2 (0.9405), SD (0.2581), F (102.7), P (1.56e-015), RMSE (0.402), Stability (0.5411) and Pearson-r (0.9397). The generated e-pharmacophores have GH scores over 0.5 and AUAC ≥ 0.7 indicated that all the pharmacophores were suitable for pharmacophore-based virtual screening. The virtual screened compounds ZINC12323179, ZINC01642724, ZINC14238006 have showed similar structural alignment as co-crystallized ligand and showed the hydrogen bonding of ligand with ASN101, SER178, THR179, VAL238, CYS241 amino acid of protein. Conclusion: The study illustrates that the ligand and structure based pharmacophoric approach is beneficial for identification of structurally diverse hits, having better binding affinity on colchicines binding site as novel anticancer agents.

Structural features of GABAA receptor antagonists: pharmacophore modeling and 3D-QSAR studies

2013 ◽  
Vol 22 (12) ◽  
pp. 5961-5972 ◽  
Author(s):  
Wei Zhang ◽  
Shuang Xia ◽  
Jinjin Ye ◽  
Yun Tang ◽  
Zhong Li ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
3D Qsar ◽  
Structural Features ◽  
Pharmacophore Modeling ◽  
Receptor Antagonists ◽  
Qsar Studies

QSAR Studies of Halogenated Pyrimidine Derivatives as Inhibitors of Human Dihydroorotate Dehydrogenase Using Modified Bee Algorithm

2018 ◽  
Vol 21 (5) ◽  
pp. 381-387 ◽  
Author(s):  
Hossein Atabati ◽  
Kobra Zarei ◽  
Hamid Reza Zare-Mehrjardi
Keyword(s):  
External Validation ◽  
Correlation Coefficients ◽  
Quantitative Structure Activity Relationship ◽  
Molecular Structures ◽  
Dihydroorotate Dehydrogenase ◽  
Pyrimidine Derivatives ◽  
Qsar Studies ◽  
Bee Algorithm ◽  
Test Sets ◽  
Leave One Out

Aim and Objective: Human dihydroorotate dehydrogenase (DHODH) catalyzes the fourth stage of the biosynthesis of pyrimidines in cells. Hence it is important to identify suitable inhibitors of DHODH to prevent virus replication. In this study, a quantitative structure-activity relationship was performed to predict the activity of one group of newly synthesized halogenated pyrimidine derivatives as inhibitors of DHODH. Materials and Methods: Molecular structures of halogenated pyrimidine derivatives were drawn in the HyperChem and then molecular descriptors were calculated by DRAGON software. Finally, the most effective descriptors for 32 halogenated pyrimidine derivatives were selected using bee algorithm. Results: The selected descriptors using bee algorithm were applied for modeling. The mean relative error and correlation coefficient were obtained as 2.86% and 0.9627, respectively, while these amounts for the leave one out−cross validation method were calculated as 4.18% and 0.9297, respectively. The external validation was also conducted using two training and test sets. The correlation coefficients for the training and test sets were obtained as 0.9596 and 0.9185, respectively. Conclusion: The results of modeling of present work showed that bee algorithm has good performance for variable selection in QSAR studies and its results were better than the constructed model with the selected descriptors using the genetic algorithm method.

Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β -Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors

2019 ◽  
Vol 16 (7) ◽  
pp. 775-784
Author(s):  
Richa Arya ◽  
Satya Prakash Gupta ◽  
Sarvesh Paliwal ◽  
Swapnil Sharma ◽  
Kirtika Madan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medical Condition ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Pyridine Derivative ◽  
Cleavage Enzyme ◽  
Bace 1

Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease. Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model. Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated. Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

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