scholarly journals 3D-QSAR and Molecular Docking Approaches for the Identification of Phyto-Inhibitors of Hsp90

2021 ◽  
Vol 11 (3) ◽  
pp. 3871-3886
Keyword(s):  
Cannabis Sativa ◽  
Three Dimensional ◽  
3D Qsar ◽  
Qsar Model ◽  
Tinospora Cordifolia ◽  
Amino Acid Residues ◽  
Client Protein ◽  
Lead Compounds ◽  
Quantitative Structure Activity Relationships ◽  
Hsp90 Client Protein

Inhibition of Hsp90 disrupts the Hsp90 client protein complex, resulting in its breakdown. Phytochemicals from reported anticancer plants were screened against the orthosteric site of Hsp90. The lead compounds were subjected to the Lipinski rule of five to evaluate their drug-likeness. Three-Dimensional Quantitative Structure-Activity Relationships (3D-QSAR), a mathematical model for the inhibition of Hsp90, was also derived. The lead compounds are guaiol from Cannabis sativa, actinidine from Anacadium occidentale, and choline from Tinospora cordifolia with docking scores of -11kcal/mol, -12.1kcal/mol, and -10.8kcal/mol, respectively. The 3D-QSAR model generated is robust and thoroughly validated with a correlation coefficient R of 0.94 and R2 of 0.950. Actinidine, choline and, guaiol are novel and potent inhibitors of Hsp90. They form interactions with key amino acid residues within the Hsp90 orthosteric site.

Computational Atom-based Three-Dimensional Quantitative Structure-Activity Relationship (3D QSAR) Model for Predicting Anti-Dengue Agents

2021 ◽  
Vol 16 (10) ◽  
pp. 50-58
Author(s):  
Ali Qusay Khalid ◽  
Vasudeva Rao Avupati ◽  
Husniza Hussain ◽  
Tabarek Najeeb Zaidan
Keyword(s):  
Dengue Fever ◽  
Three Dimensional ◽  
3D Qsar ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Activity Relationship ◽  
Quantitative Structure ◽  
Contour Maps ◽  
Structure Activity ◽  
Bioactive Ligands

Dengue fever is a viral infection spread by the female mosquito Aedes aegypti. It is a virus spread by mosquitoes found all over the tropics with risk levels varying depending on rainfall, relative humidity, temperature and urbanization. There are no specific medications that can be used to treat the condition. The development of possible bioactive ligands to combat Dengue fever before it becomes a pandemic is a global priority. Few studies on building three-dimensional quantitative structure-activity relationship (3D QSAR) models for anti-dengue agents have been reported. Thus, we aimed at building a statistically validated atom-based 3D-QSAR model using bioactive ligands reported to possess significant anti-dengue properties. In this study, the Schrodinger PhaseTM atom-based 3D QSAR model was developed and was validated using known anti-dengue properties as ligand data. This model was also tested to see if there was a link between structural characteristics and anti-dengue activity of a series of 3-acyl-indole derivatives. The established 3D QSAR model has strong predictive capacity and is statistically significant [Model: R2 Training Set = 0.93, Q2 (R2 Test Set) = 0.72]. In addition, the pharmacophore characteristics essential for the reported anti-dengue properties were explored using combined effects contour maps (coloured contour maps: blue: positive potential and red: negative potential) of the model. In the pathway of anti-dengue drug development, the model could be included as a virtual screening method to predict novel hits.

scholarly journals Structural investigations of CXCR2 receptor antagonists by CoMFA, CoMSIA and flexible docking studies

2012 ◽  
Vol 62 (3) ◽  
pp. 287-304 ◽  
Author(s):  
Shravan Kumar Gunda ◽  
Rohith Kumar Anugolu ◽  
Sri Ramya Tata ◽  
Saikh Mahmood
Keyword(s):  
Standard Error ◽  
Three Dimensional ◽  
3D Qsar ◽  
Homology Model ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Field Analysis ◽  
Structural Investigations ◽  
Qsar Analysis ◽  
Qsar Studies

= Three-dimensional quantitative structure activity relationship (3D QSAR) analysis was carried out on a et of 56 N,N’-diarylsquaramides, N,N’-diarylureas and diaminocyclobutenediones in order to understand their antagonistic activities against CXCR2. The studies included comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Models with good predictive abilities were generated with CoMFA q2 0.709, r2 (non-cross-validated square of correlation coefficient) = 0.951, F value = 139.903, r2 bs = 0.978 with five components, standard error of estimate = 0.144 and the CoMSIA q2 = 0.592, r2 = 0.955, F value = 122.399, r2 bs = 0.973 with six components, standard error of estimate = 0.141. In addition, a homology model of CXCR2 was used for docking based alignment of the compounds. The most active compound then served as a template for alignment of the remaining structures. Further, mapping of contours onto the active site validated each other in terms of residues involved with reference to the respective contours. This integrated molecular docking based alignment followed by 3D QSAR studies provided a further insight to support the structure-based design of CXCR2 antagonistic agents with improved activity profiles. Furthermore, in silico screening was adapted to the QSAR model in order to predict the structures of new, potentially active compounds.

scholarly journals A Modified 3D-QSAR Model Based on Ideal Point Method and Its Application in the Molecular Modification of Plasticizers with Flame Retardancy and Eco-Friendliness

Polymers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 1942
Author(s):  
Haigang Zhang ◽  
Chengji Zhao ◽  
Hui Na
Keyword(s):  
Flame Retardancy ◽  
Evaluation Method ◽  
Comprehensive Evaluation ◽  
Ideal Point ◽  
Three Dimensional ◽  
3D Qsar ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Point Method ◽  
Contour Maps

The addition of plasticizers makes plastics flammable, and thus, poses a potential risk to the environment. In previous researches, plasticizers with flame retardancy had been synthesized, but their eco-friendliness had not been tested or described. Thus, in this paper, eco-friendliness plasticizers with flame retardancy were designed based on phthalic acid esters (PAEs), which are known as common plasticizers and major plastic additives. For a comprehensive analysis, such as flammability, biotoxicity, and enrichment effects, 17 PAEs’ comprehensive evaluation values were calculated based on the ideal point method. Further, a multi-effect three-dimensional quantitative structure-activity relationship (3D-QSAR) model of PAEs’ flammability, biotoxicity and enrichment effects was constructed. Thus, 18 dimethyl phthalate (DMP) derivatives and 20 diallyl phthalate (DAP) derivatives were designed based on three-dimensional contour maps. Through evaluation of eco-friendliness and flammability, six eco-friendly PAE derivatives with flame retardancy were screened out. Based on contour maps analysis, it was confirmed that the introduction of large groups and hydrophobic groups was beneficial to the simultaneous improvement of PAEs’ comprehensive effects, and multiple effects. In addition, the group properties were correlated significantly with improved degrees of the comprehensive effects of corresponding PAE derivatives, confirming the feasibility of the comprehensive evaluation method and modified scheme.

THREE-DIMENSIONAL QSAR MODELING BENZIMIDAZOLE ANALOGUES USING THE K-NEAREST NEIGHBOR METHOD

INDIAN DRUGS ◽  
2019 ◽  
Vol 56 (12) ◽  
pp. 62-67
Author(s):  
M. C Sharma ◽  
◽  
D. V. Kohli
Keyword(s):  
Nearest Neighbor ◽  
Three Dimensional ◽  
Antihypertensive Agents ◽  
3D Qsar ◽  
Good Alternative ◽  
Qsar Model ◽  
Field Analysis ◽  
K Nearest Neighbor ◽  
Qsar Modeling ◽  
Qsar Studies

We undertook the three-dimensional (3D) QSAR studies of a series of benzimidazole analogues to elucidate the structural properties required for angiotensin II. The 3D-QSAR studies were performed using the stepwise, simulated annealing (SA) and genetic algorithm (GA) selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q2 = 0.8216 and a pred_r2 = 0.7852 were obtained. The 3D QSAR model is expected to provide a good alternative to predict the biological activity prior to synthesis as antihypertensive agents.

scholarly journals 3D-QSAR and Docking Studies of a Series ofβ-Carboline Derivatives as Antitumor Agents of PLK1

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Jahan B. Ghasemi ◽  
Valentin Davoudian
Keyword(s):  
Antitumor Agents ◽  
Three Dimensional ◽  
Human Tumor ◽  
3D Qsar ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Docking Studies ◽  
Human Tumor Cell Lines ◽  
Qsar Analysis ◽  
Leave One Out

An alignment-free, three dimensional quantitative structure-activity relationship (3D-QSAR) analysis has been performed on a series ofβ-carboline derivatives as potent antitumor agents toward HepG2 human tumor cell lines. A highly descriptive and predictive 3D-QSAR model was obtained through the calculation of alignment-independent descriptors (GRIND descriptors) using ALMOND software. For a training set of 30 compounds, PLS analyses result in a three-component model which displays a squared correlation coefficient (r2) of 0.957 and a standard deviation of the error of calculation (SDEC) of 0.116. Validation of this model was performed using leave-one-out,q2looof 0.85, and leave-multiple-out. This model gives a remarkably highr2pred(0.66) for a test set of 10 compounds. Docking studies were performed to investigate the mode of interaction betweenβ-carboline derivatives and the active site of the most probable anticancer receptor, polo-like kinase protein.

scholarly journals Docking and 3D QSAR Studies on p38α MAP Kinase Inhibitors

2011 ◽  
Vol 8 (4) ◽  
pp. 1596-1605
Author(s):  
Mohan Babu Jatavath ◽  
Sree Kanth Sivan ◽  
Yamini Lingala ◽  
Vijjulatha Manga
Keyword(s):  
Map Kinase ◽  
Kinase Inhibitors ◽  
Inflammatory Diseases ◽  
Biological Activities ◽  
Three Dimensional ◽  
3D Qsar ◽  
Qsar Model ◽  
Chemotherapeutic Agents ◽  
Field Analysis ◽  
Qsar Studies

The p38 signaling cascade has emerged as an attractive target for the design of novel chemotherapeutic agents for the treatment of inflammatory diseases. Three dimensional quantitative structure- activity relationship (3D- QSAR) studies were performed on a series of 25, 2-aminothiazole analogs as inhibitors of p38α mitogen activated protein (MAP) kinase. The docking results provided a reliable conformational alignment scheme for the 3D-QSAR model. The 3D-QSAR model showed very good statistical results namely q2, r2and r2predvalues for both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The CoMFA and CoMSIA models & docking results provided the most significant correlation of steric, electrostatic, hydrophobic,H-bond donor,H-bond acceptor fields with biological activities and the provided values were in good agreement with the experimental results. The information rendered from molecular modeling studies gave valuable clues to optimize the lead and design new potential inhibitors.

scholarly journals Computer-aided Design of Peptidomimetic Inhibitors of falcipain-3: QSAR and Pharmacophore Models

2021 ◽  
Author(s):  
Boris D. Bekono ◽  
Akori Esmel ◽  
Brice Dali ◽  
Fidele Ntie-Kang ◽  
Melalie Keita ◽  
...  
Keyword(s):  
Computer Aided Design ◽  
Molecular Design ◽  
Structural Information ◽  
Three Dimensional ◽  
Pharmacophore Model ◽  
Combinatorial Libraries ◽  
3D Qsar ◽  
3D Models ◽  
Qsar Model ◽  
Computer Aided

In this work antiparasitic peptidomimetics inhibitors (PEP) of falcipain-3 (FP3) of Plasmodium falciparum (Pf) have been proposed using structure-based and computer-aided molecular design. Beginning with the crystal structure of PfFP3-K11017 complex (PDB ID: 3BWK), three-dimensional (3D) models of FP3-PEPx complexes with known activities (IC50exp) were prepared by in situ modification, based on molecular mechanics and implicit solvation to compute Gibbs free energies (GFE) of inhibitor-FP3 complex formation. This resulted in a quantitative structure-activity relationships (QSAR) model based on a linear correlation between computed GFE (ΔΔGcomp) and the experimentally measured IC50exp: (pIC50exp=-(IC50exp/109) =-0.4517×∆∆Gcomp+4.0865 ; R2 = 0.89). Apart from the structure-based relationship, a ligand-based quantitative pharmacophore model (PH4) of novel PEP analogs where substitutions were directed by comparative analysis of the active site interactions was derived using the proposed bound conformations of the PEPx. This provided structural information useful for the design of virtual combinatorial libraries (VL), which was virtually screened based on the 3D-QSAR PH4. The end results were predictory inhibitory activities falling within the low nanomolar concentration range.

CoMFA, CoMSIA and HQSAR Analysis of 3-aryl-3-ethoxypropanoic Acid Derivatives as GPR40 Modulators

2020 ◽  
Vol 17 (1) ◽  
pp. 100-118
Author(s):  
Krishna A. Gajjar ◽  
Anuradha K. Gajjar
Keyword(s):  
Biological Activity ◽  
Structural Information ◽  
Three Dimensional ◽  
3D Qsar ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Docking Studies ◽  
Statistical Parameters ◽  
Qsar Study ◽  
Negative Contribution

Background: Human GPR40 receptor, also known as free fatty-acid receptor 1, is a Gprotein- coupled receptor that binds long chain free fatty acids to enhance glucose-dependent insulin secretion. In order to improve the resistance and efficacy, computational tools were applied to a series of 3-aryl-3-ethoxypropanoic acid derivatives. A relationship between the structure and biological activity of these compounds, was derived using a three-dimensional quantitative structure-activity relationship (3D-QSAR) study using CoMFA, CoMSIA and two-dimensional QSAR study using HQSAR methods. Methods: Building the 3D-QSAR models, CoMFA, CoMSIA and HQSAR were performed using Sybyl-X software. The ratio of training to test set was kept 70:30. For the generation of 3D-QSAR model three different alignments were used namely, distill, pharmacophore and docking based alignments. Molecular docking studies were carried out on designed molecules using the same software. Results: Among all the three methods used, Distill alignment was found to be reliable and predictive with good statistical results. The results obtained from CoMFA analysis q2, r2cv and r2 pred were 0.693, 0.69 and 0.992 respectively and in CoMSIA analysis q2, r2cv and r2pred were 0.668, 0.648 and 0.990. Contour maps of CoMFA (lipophilic and electrostatic), CoMSIA (lipophilic, electrostatic, hydrophobic, and donor) and HQSAR (positive & negative contribution) provided significant insights i.e. favoured and disfavoured regions or positive & negative contributing fragments with R1 and R2 substitutions, which gave hints for the modifications required to design new molecules with improved biological activity. Conclusion: 3D-QSAR techniques were applied for the first time on the series 3-aryl-3- ethoxypropanoic acids. All the models (CoMFA, CoMSIA and HQSAR) were found to be satisfactory according to the statistical parameters. Therefore such a methodology, whereby maximum structural information (from ligand and biological target) is explored, gives maximum insights into the plausible protein-ligand interactions and is more likely to provide potential lead candidates has been exemplified from this study.

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