scholarly journals Structural Requirements of N-alpha-Mercaptoacetyl Dipeptide (NAMdP) Inhibitors of Pseudomonas Aeruginosa Virulence Factor LasB: 3D-QSAR, Molecular Docking, and Interaction Fingerprint Studies

2019 ◽  
Vol 20 (24) ◽  
pp. 6133 ◽  
Author(s):  
José Luis Velázquez-Libera ◽  
Juliana Andrea Murillo-López ◽  
Alexander F. de la Torre ◽  
Julio Caballero
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Hydrogen Bond ◽  
Molecular Docking ◽  
Binding Site ◽  
Virulence Factor ◽  
External Validation ◽  
3D Qsar ◽  
Interaction Patterns ◽  
Ligand Interaction ◽  
Hydrogen Bond Acceptor

The zinc metallopeptidase Pseudomonas elastase (LasB) is a virulence factor of Pseudomonas aeruginosa (P. aeruginosa), a pathogenic bacterium that can cause nosocomial infections. The present study relates the structural analysis of 118 N-alpha-mercaptoacetyl dipeptides (NAMdPs) as LasB inhibitors. Field-based 3D-QSAR and molecular docking methods were employed to describe the essential interactions between NAMdPs and LasB binding sites, and the chemical features that determine their differential activities. We report a predictive 3D-QSAR model that was developed according to the internal and external validation tests. The best model, including steric, electrostatic, hydrogen bond donor, hydrogen bond acceptor, and hydrophobic fields, was found to depict a three-dimensional map with the local positive and negative effects of these chemotypes on the LasB inhibitory activities. Furthermore, molecular docking experiments yielded bioactive conformations of NAMdPs inside the LasB binding site. The series of NAMdPs adopted a similar orientation with respect to phosphoramidon within the LasB binding site (crystallographic reference), where the backbone atoms of NAMdPs are hydrogen-bonded to the LasB residues N112, A113, and R198, similarly to phosphoramidon. Our study also included a deep description of the residues involved in the protein–ligand interaction patterns for the whole set of NAMdPs, through the use of interaction fingerprints (IFPs).

Development of Structure Activity Correlation Model on Aroylindole Derivatives as Anticancer Agents

2018 ◽  
Vol 15 (2) ◽  
pp. 143-153
Author(s):  
Vijay K. Patel ◽  
Harish Rajak
Keyword(s):  
Hydrogen Bond ◽  
Biological Activity ◽  
Molecular Docking ◽  
Covalent Binding ◽  
Research Work ◽  
3D Qsar ◽  
Pharmacophore Mapping ◽  
Hydrogen Bond Acceptor ◽  
Computational Approaches ◽  
Structure Activity

Background: Aroylindole derivatives, the structural analogs of Combretastatin A-4 has been found to possess potent growth inhibitory activity on several cancer cell lines due to its excellent antitumor and antivascular activities. The aim of present research work is to identify lead and establish structure activity correlation of trimethoxyaroylindole derivatives, using integrated ligand and structure based computational approaches. Materials and Methods: A correlation between structure and biological activity was established using computational approaches i.e., structure activity correlation by pharmacophore and atom based 3D QSAR, molecular docking and energetic based pharmacophore mapping studies of trimethoxyaroylindole derivatives. Results and Discussion: The 3D-QSAR on trimethoxyaroylindole derivatives generated and showed best statistical result for CPHs AAARR.182 was validated by Q2 (0.6929), R2 (0.82). The Comp. 1 of the training set was employed as template for hydrogen bond donor, hydrophobic and hydrogen bond acceptor field prediction features and visualization of the 3D-QSAR model provides details of relationship between structure and biological activity of trimethoxyaroylindole derivatives. Pharmacophore model was developed by Phase and e-pharmacophore on comp. 1, the trimethoxy group with ring A, keto group, N-H group with ring B and ring C are pharmacophoric group important for the lead generation and coincide with various chemical features that may facilitate non-covalent binding between the ligand and its target receptor. Molecular docking studies showed critical interactions between Cys241, Val318 and meta, para-methoxy group at ring A while and Thr179 and NH of indole (distance 3.5 Å). The para position of trimethoxyphenyl ring bind to SH group of CYS 241 receptor molecule via hydrogen bond. Conclusion: The lead identification and establish structure activity correlation of trimethoxyaroylindole derivatives, were performed using integrated ligand and structure based computational approaches i.e., atom based 3D QSAR and pharmacophore study, molecular docking, energetic based pharmacophore mapping studies showed promising results. The outcomes of present studies could be utilized for the design of novel aroylindole derivatives including its lead optimization as potential anticancer agent.

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.

Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods

2021 ◽  
Vol 18 ◽  
Author(s):  
Jelena Bošković ◽  
Dušan Ružić ◽  
Olivera Čudina ◽  
Katarina Nikolic ◽  
Vladimir Dobričić
Keyword(s):  
Molecular Docking ◽  
External Validation ◽  
Three Dimensional ◽  
3D Qsar ◽  
Quantitative Structure Activity Relationship ◽  
Docking Studies ◽  
Qsar Analysis ◽  
In Silico Admet ◽  
Cox 2 ◽  
Lox Inhibitors

Background: Inflammation is common pathogenesis of many diseases progression, such as malignancy, cardiovascular and rheumatic diseases. The inhibition of the synthesis of inflammatory mediators by modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways provides a challenging strategy for the development of more effective drugs. Objective: The aim of this study was to design dual COX-2 and 5-LOX inhibitors with iron-chelating properties using a combination of ligand-based (three-dimensional quantitative structure-activity relationship (3D-QSAR)) and structure-based (molecular docking) methods. Methods: The 3D-QSAR analysis was applied on a literature dataset consisting of 28 dual COX-2 and 5-LOX inhibitors in Pentacle software. The quality of developed COX-2 and 5-LOX 3D-QSAR models were evaluated by internal and external validation methods. The molecular docking analysis was performed in GOLD software, while selected ADMET properties were predicted in ADMET predictor software. Results: According to the molecular docking studies, the class of sulfohydroxamic acid analogues, previously designed by 3D-QSAR, was clustered as potential dual COX-2 and 5-LOX inhibitors with iron-chelating properties. Based on the 3D-QSAR and molecular docking, 1j, 1g, and 1l were selected as the most promising dual COX-2 and 5-LOX inhibitors. According to the in silico ADMET predictions, all compounds had an ADMET_Risk score less than 7 and a CYP_Risk score lower than 2.5. Designed compounds were not estimated as hERG inhibitors, and 1j had improved intrinsic solubility (8.704) in comparison to the dataset compounds (0.411-7.946). Conclusion: By combining 3D-QSAR and molecular docking, three compounds (1j, 1g, and 1l) are selected as the most promising designed dual COX-2 and 5-LOX inhibitors, for which good activity, as well as favourable ADMET properties and toxicity, are expected.

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.

Identification of new checkpoint kinase-1 (Chk1) inhibitors by docking, 3D-QSAR, and pharmacophore-modeling methods

2012 ◽  
Vol 90 (8) ◽  
pp. 675-692 ◽  
Author(s):  
Premlata K. Ambre ◽  
Raghuvir R. S. Pissurlenkar ◽  
Evans C. Coutinho ◽  
Radhakrishnan P. Iyer
Keyword(s):  
Hydrogen Bond ◽  
3D Qsar ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Hydrogen Bond Donor ◽  
Hydrogen Bond Acceptor ◽  
Checkpoint Kinase ◽  
Checkpoint Kinase 1 ◽  
Qsar Models ◽  
Potential Inhibitors

Inhibition of checkpoint kinase-1 (Chk1) by small molecules is of great therapeutic interest in the field of oncology and for understanding cell-cycle regulations. This paper presents a model with elements from docking, pharmacophore mapping, the 3D-QSAR approaches CoMFA, CoMSIA and CoRIA, and virtual screening to identify novel hits against Chk1. Docking, 3D-QSAR (CoRIA, CoMFA and CoMSIA), and pharmacophore studies delineate crucial site points on the Chk1 inhibitors, which can be modified to improve activity. The docking analysis showed residues in the proximity of the ligands that are involved in ligand–receptor interactions, whereas CoRIA models were able to derive the magnitude of these interactions that impact the activity. The ligand-based 3D-QSAR methods (CoMFA and CoMSIA) highlight key areas on the molecules that are beneficial and (or) detrimental for activity. The docking studies and 3D-QSAR models are in excellent agreement in terms of binding-site interactions. The pharmacophore hypotheses validated using sensitivity, selectivity, and specificity parameters is a four-point model, characterized by a hydrogen-bond acceptor (A), hydrogen-bond donor (D), and two hydrophobes (H). This map was used to screen a database of 2.7 million druglike compounds, which were pruned to a small set of potential inhibitors by CoRIA, CoMFA, and CoMSIA models with predicted activity in the range of 8.5–10.5 log units.

scholarly journals Identification of novel and structurally diverse N-Methyl-D-Aspartate Receptor Antagonists: Successful Application of Pharmacophore Modeling, Virtual Screening and Molecular Docking

2018 ◽  
Author(s):  
Mukta Sharma ◽  
Anupama Mittal ◽  
Aarti Singh ◽  
Ashwin K. Jainarayanan ◽  
Sarvesh Kumar Paliwal
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Nmda Receptor ◽  
Virtual Screening ◽  
Alzheimer Disease ◽  
Receptor Antagonist ◽  
In Silico ◽  
Nmda Receptor Antagonist ◽  
Receptor Antagonists ◽  
Hydrogen Bond Acceptor

ABSTRACTIn view of “excitotoxic” effects of glutamate, wherein excessive excitatory input causes increase in intracellular Ca2+ and ultimately cell death, NMDA receptor has emerged as an important target for treatment and prevention of several neurological disorders, like Alzheimer disease. Prompted by the successful application of in-silico pharmacophore-based virtual screening in lead identification, we have made an effort to implement in-silico protocols to identify novel NMDA receptor antagonist. A series of novel benzo[b]quinolizinium cations as NMDA receptor antagonists have been used as a starting point to develop prognostic pharmacophore models. The most predictive pharmacophore model (hypothesis 1), consisting of four features, namely, one hydrogen bond acceptor, one hydrophobic and two ring aromatic, showed a correlation (r) of 0.89, root mean square of 0.259, and the cost difference of 43.01 bits between null and fixed cost. The model was thoroughly validated and subjected to a chemical database search, which lead to the identification of 400 hits from NCI and Maybridge databases which were checked for Lipinski’s violation and predictive potency.This reduced the list to 10 compounds, out of which, two most potent compounds were subjected to molecular docking using Libdock software and interestingly, all the docked conformations showed hydrogen bond interactions with important amino acids Tyr214, His88, Thr174, Val169 and Arg121. In summary, through our validated pharmacophore-based virtual screening protocol, we have identified two potent, structurally diverse, druggable and novel NMDA receptor antagonist which might be of great help to address the unmet medical need of Alzheimer disease.

Improved 3D-QSAR Prediction by Multiple-Conformational Alignments and Molecular Docking Studies to Design and Discover HIV-I Protease Inhibitors

2020 ◽  
Vol 18 ◽  
Author(s):  
Paresh K. Patel ◽  
Hardik G. Bhatt
Keyword(s):  
Hydrogen Bond ◽  
Drug Design ◽  
Protease Inhibitors ◽  
Correlation Coefficient ◽  
3D Qsar ◽  
Qsar Model ◽  
Hydrogen Bond Acceptor ◽  
Contour Maps ◽  
Validation Parameters ◽  
Predicted Values

Background: Inhibition of HIV-I protease enzyme is a strategic step for providing better treatment in retrovirus infections which avoids resistance and has less toxicities. Objectives: In the course of our research to discover new and potent protease inhibitors, 3D-QSAR (CoMFA and CoMSIA) models were generated using 3 different alignment techniques including multifit alignment, docking based and Distill based alignment for 63 compounds. Novel molecules were designed from the output of this study Methods: Total 3 alignment methods were used to generate CoMFA and CoMSIA models. A Distill based alignment method was considered a better method according to different validation parameters. A 3D-QSAR model was generated and contour maps were discussed. The biological activity of designed molecules were predicted using generated QSAR model to validate QSAR. The newly designed molecules were docked to predict binding affinity. Results: In CoMFA, leave one out cross validated coefficient (q 2 ), conventional coefficient (r 2 ) and predicted correlation coefficient (r 2 Predicted) values were found to be 0.721, 0.991 and 0.780, respectively. The best obtained CoMSIA model also had significant cross validated coefficient (q 2 ), conventional coefficient (r 2 ) and predicted correlation coefficient (r 2 Predicted) values of 0.714, 0.987 and 0.721, respectively. Steric and electrostatic contour maps generated from CoMFA and hydrophobic and hydrogen bond donor and hydrogen bond acceptor contour maps from CoMSIA models were used to design new and bioactive protease inhibitors by incorporating bioisosterism and knowledge based structure activity relationship. Conclusion: The results from both these approaches, ligand based drug design and structure based drug design, are adequate and promising to discover protease inhibitors.

scholarly journals Interaction of Irbesartan with Bovine Hemoglobin Using Spectroscopic Techniques and Molecular Docking

2012 ◽  
Vol 27 ◽  
pp. 119-128 ◽  
Author(s):  
Ai-Ping Yang ◽  
Mei-Hua Ma ◽  
Xiao-Hua Li ◽  
Mao-Yun Xue
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Binding Site ◽  
Binding Free Energy ◽  
Protein Secondary Structure ◽  
Cd Spectroscopy ◽  
Electrostatic Energy ◽  
Bovine Hemoglobin ◽  
Spectroscopic Techniques ◽  
Hydrogen Bond Formation

The binding of irbesartan to bovine hemoglobin (BHb) has been investigated for the first time by using UV-Vis absorption, fluorescence, circular dichroism (CD), and molecular docking. The binding site numbernand binding constantKwere calculated to be 1 and , respectively. The alternations of protein secondary structure in the presence of irbesartan was demonstrated using CD spectroscopy. Furthermore, molecular docking indicated that irbesartan could bind to the site 2 of BHb. The analysis of the binding site of irbesartan within the BHb molecule suggested that hydrophobic interaction, hydrogen bond formation, and electrostatic interaction could account for the binding of irbesartan. The hydrogen bond of irbesartan with His87 in the C chain of BHb has been formed. The electrostatic energy, van der Waals energy, and binding free energy were calculated to be −460.3, −224.2, and−684.5 kcal, respectively.

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