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

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.

Download Full-text

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

Journal of Theoretical and Computational Chemistry ◽

10.1142/s0219633610006146 ◽

2010 ◽

Vol 09 (06) ◽

pp. 975-991 ◽

Cited By ~ 10

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.

Download Full-text

In Silico Screening of Novel α1-GABAA Receptor PAMs towards Schizophrenia Based on Combined Modeling Studies of Imidazo [1,2-a]-Pyridines

International Journal of Molecular Sciences ◽

10.3390/ijms22179645 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9645

Author(s):

Xiaojiao Zheng ◽

Chenchen Wang ◽

Na Zhai ◽

Xiaogang Luo ◽

Genyan Liu ◽

...

Keyword(s):

Gabaa Receptor ◽

Rational Design ◽

Hydrophobic Interactions ◽

Three Dimensional ◽

Pharmacophore Model ◽

3D Qsar ◽

Md Simulations ◽

Binding Pocket ◽

Pharmacophore Modeling ◽

Topomer Search

The ionotropic GABAA receptor (GABAAR) has been proven to be an important target of atypical antipsychotics. A novel series of imidazo [1,2-a]-pyridine derivatives, as selective positive allosteric modulators (PAMs) of α1-containing GABAARs with potent antipsychotic activities, have been reported recently. To better clarify the pharmacological essentiality of these PAMs and explore novel antipsychotics hits, three-dimensional quantitative structure–activity relationships (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) were performed on 33 imidazo [1,2-a]-pyridines. The constructed 3D-QSAR models exhibited good predictive abilities. The dockings results and MD simulations demonstrated that hydrogen bonds, π–π stackings, and hydrophobic interactions play essential roles in the binding of these novel PAMs in the GABAAR binding pocket. Four hit compounds (DS01–04) were then screened out by the combination of the constructed models and computations, including the pharmacophore model, Topomer Search, molecular dockings, ADME/T predictions, and MD simulations. The compounds DS03 and DS04, with higher docking scores and better predicted activities, were also found to be relatively stable in the binding pocket by MD simulations. These results might provide a significant theoretical direction or information for the rational design and development of novel α1-GABAAR PAMs with antipsychotic activities.

Download Full-text

Searching for novel Janus kinase-2 inhibitors using a combination of pharmacophore modeling, 3D QSAR studies and virtual screening

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557516666161024144837 ◽

2016 ◽

Vol 16 (999) ◽

pp. 1-1

Author(s):

Eleni Vrontaki ◽

Georgia Melagraki ◽

Antreas Afantitis ◽

Thomas Mavromoustakos ◽

George Kolliasc

Keyword(s):

Virtual Screening ◽

3D Qsar ◽

Pharmacophore Modeling ◽

Janus Kinase ◽

Janus Kinase 2 ◽

Qsar Studies

Download Full-text

Ligand-based and e-pharmacophore modeling, 3D-QSAR and hierarchical virtual screening to identify dual inhibitors of spleen tyrosine kinase (Syk) and janus kinase 3 (JAK3)

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2016.1240108 ◽

2016 ◽

Vol 35 (14) ◽

pp. 3043-3060 ◽

Cited By ~ 6

Author(s):

Maninder Kaur ◽

Om Silakari

Keyword(s):

Virtual Screening ◽

Tyrosine Kinase ◽

3D Qsar ◽

Pharmacophore Modeling ◽

Janus Kinase ◽

Spleen Tyrosine Kinase ◽

Dual Inhibitors ◽

Janus Kinase 3

Download Full-text

Searching for Novel Janus Kinase-2 Inhibitors Using a Combination of Pharmacophore Modeling, 3D-QSAR Studies and Virtual Screening

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557516666160919163930 ◽

2017 ◽

Vol 17 (3) ◽

pp. 268-294 ◽

Cited By ~ 6

Author(s):

Eleni Vrontaki ◽

Georgia Melagraki ◽

Antreas Afantitis ◽

Thomas Mavromoustakos ◽

George Kollias

Keyword(s):

Virtual Screening ◽

3D Qsar ◽

Pharmacophore Modeling ◽

Janus Kinase ◽

Janus Kinase 2 ◽

Qsar Studies

Download Full-text

Molecular modeling on the identification of potential Janus Kinase 3 (JAK3) inhibitor based on the Indonesian Medicinal Plant Database

Journal of Mathematical and Fundamental Sciences ◽

10.5614/j.math.fund.sci.2020.52.3.2 ◽

2020 ◽

Vol 52 (3) ◽

pp. 276-285

Author(s):

Muhammad Arba ◽

Sanang Nur Safitri ◽

Andry Nur Hidayat ◽

Arry Yanuar ◽

Muhammad Sulaiman Zubair ◽

...

Keyword(s):

Md Simulation ◽

Simulation Analysis ◽

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Binding Energies ◽

Janus Kinase ◽

Great Promise ◽

Energy Calculation ◽

Jak3 Inhibitor ◽

Janus Kinase 3

The Janus tyrosine kinases (JAKs) have shown great promise as therapeutic protein targets in the treatment of cancer and inflammation diseases. This study used pharmacophore modeling to identify potential inhibitors of Janus kinase 3 (JAK3). A pharmacophore model was developed based on a known JAK3 inhibitor (1NX) and was employed to search for potential JAK3 inhibitors against Indonesian herbal compounds. Among 28 hit molecules that were identified and subjected to a molecular docking protocol against JAK3, the three compounds that had the highest affinities toward JAK3 were camelliaside B, 3-O-galloylepicatechin-(4beta-6)-epicatechin-3-O-gallate, and mesuaferrone B. These were then each subjected to a 50-ns molecular dynamics (MD) simulation. Analysis of RMSD and RMSF values indicated that the three compounds reached stability during the MD simulation. Interestingly, all three compounds had lower binding energies than 1NX against JAK3, as predicted by the MM-PBSA binding energy calculation.

Download Full-text

Pharmacophore Modeling and 3D QSAR Studies of Novel Human Carbonic Anhydrase IX Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/15701808113100990026 ◽

2013 ◽

Vol 10 (9) ◽

pp. 808-816

Author(s):

Kalyan Sethi ◽

Saurabh Verma

Keyword(s):

Carbonic Anhydrase ◽

3D Qsar ◽

Pharmacophore Modeling ◽

Carbonic Anhydrase Ix ◽

Qsar Studies ◽

Human Carbonic Anhydrase

Download Full-text

3D-QSAR Studies of S-DABO Derivatives as Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180810112321 ◽

2019 ◽

Vol 16 (8) ◽

pp. 868-881

Author(s):

Yueping Wang ◽

Jie Chang ◽

Jiangyuan Wang ◽

Peng Zhong ◽

Yufang Zhang ◽

...

Keyword(s):

Reverse Transcriptase ◽

Three Dimensional ◽

Predictive Ability ◽

3D Qsar ◽

Binding Mode ◽

Quantitative Structure Activity Relationship ◽

Field Analysis ◽

Reverse Transcriptase Inhibitors ◽

Qsar Studies ◽

Hiv 1

Background: S-dihydro-alkyloxy-benzyl-oxopyrimidines (S-DABOs) as non-nucleoside reverse transcriptase inhibitors have received considerable attention during the last decade due to their high potency against HIV-1. Methods: In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) of a series of 38 S-DABO analogues developed in our lab was studied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The Docking/MMFF94s computational protocol based on the co-crystallized complex (PDB ID: 1RT2) was used to determine the most probable binding mode and to obtain reliable conformations for molecular alignment. Statistically significant CoMFA (q2=0.766 and r2=0.949) and CoMSIA (q2=0.827 and r2=0.974) models were generated using the training set of 30 compounds on the basis of hybrid docking-based and ligand-based alignment. Results: The predictive ability of CoMFA and CoMSIA models was further validated using a test set of eight compounds with predictive r2 pred values of 0.843 and 0.723, respectively. Conclusion: The information obtained from the 3D contour maps can be used in designing new SDABO derivatives with improved HIV-1 inhibitory activity.

Download Full-text