Integrated computational analysis on some Indolo-quinoline derivatives for the development of novel antiplasmodium agents: CoMFA, Pharmacophore mapping, molecular docking and ADMET studies

2021 ◽  
Vol 16 ◽  
Author(s):  
Chaitali Mallick ◽  
Mitali Mishra ◽  
Vivek Asati ◽  
Varsha Kashaw ◽  
Ratnesh Das ◽  
...  
Keyword(s):  
Least Squares Method ◽  
Antimalarial Activity ◽  
3D Qsar ◽  
Docking Study ◽  
Field Analysis ◽  
Quinoline Derivatives ◽  
Pharmacophore Mapping ◽  
Hydrogen Bond Acceptor ◽  
Antimalarial Agents ◽  
Functional Features

Background: The development of multi-resistant strains of the Plasmodium parasite has become a global problem. Therefore, designing of new antimalarial agents is an exclusive solution.: Objective: To improve the activity and identify potentially efficacious new antimalarial agents, integrated computational perspectives such as pharmacophore mapping, 3D-QSAR and docking study have been applied to a series of indolo-quinoline derivatives. Methods: The pharmacophore mapping generated various hypotheses based on key functional features and the best hypothesis ADRRR_1 revealed that indolo-quinoline scaffold is essential for antimalarial activity. 3D-QSAR model was established based on CoMFA and CoMSIA models by using 30 indolo-quinoline analogues as training set and the rest of 19 as test set. Results: The molecular field analysis (MFA) with PLS (partial least-squares) method was used to develop significant CoMFA (q2=0.756, r2=0.996) and CoMSIA (q2=0.703, r2=0.812) models. The CoMFA and CoMSIA models showed good predictive ability with r2pred values of 0.9623 and 0.9214 respectively. Docking studies were performed by using pfLDH to identify structural insight into the active site and results signify that the quinoline nitrogen acts as a hydrogen bond acceptor region to facilitate interaction with Glu122. Finally, designed molecules were screened through the ADMET tool to evaluate the pharmacokinetic and drug-likeness parameters. Conclusion: Thus, these studies suggested that established models have good predictability and would help in the optimization of newly designed molecules that may produce potent antimalarial activity.

scholarly journals 3D QSAR AND DOCKING STUDY OF INDOLE DERIVATIVES AS SELECTIVE COX-2 INHIBITORS

2019 ◽  
pp. 84-92
Author(s):  
Rajashree Chavan ◽  
HARINATH MORE
Keyword(s):  
Binding Affinity ◽  
Correlation Coefficient ◽  
3D Qsar ◽  
Docking Study ◽  
Field Analysis ◽  
Indole Derivatives ◽  
K Nearest Neighbor ◽  
Qsar Study ◽  
Cox 2 ◽  
Anti Inflammatory

Objective: Non-steroidal anti-inflammatory agents (NSAIDs) continue to be one of the most widely used groups of therapeutic agents. QSAR (quantitative structure-activity relationship) approach is a very useful and widespread technique for drug design. 3D QSAR facilitates evaluation of three-dimensional molecular fields around molecules and generates a relationship of these fields' values with the activity. Methods: 3D QSAR study was performed on selected twenty-four compounds from synthesized indole derivatives using the stepwise variable selection k-nearest neighbor (kNN) molecular field analysis approach for indicating the contribution of the steric and electronic field for activity. The docking study was performed to further confirm the binding affinity of synthesized molecules (ligands) to COX-2 enzyme as well as to study binding nature. Results: Statistically significant model was generated using VLife Molecular Design Suite 3.5 software with cross-validated correlation coefficient q2 of 0.9461 and high predictive correlation coefficient (Pred_r2) of 0.8782 indicating that the model is robust. The results of docking study suggest that the synthesized compounds have a comparable binding affinity with the COX-2 enzyme. Conclusion: The present study may prove to be helpful in the development and optimization of existing indole derivatives as anti-inflammatory agents with selective COX-2 inhibition.

scholarly journals Synthesis, Molecular Docking, and Evaluation of Some New Curcumin Analogs as Antimalarial Agents

2021 ◽  
Vol 21 (2) ◽  
pp. 452
Author(s):  
Endang Astuti ◽  
Tri Joko Raharjo ◽  
Putra Boang Manalu ◽  
Ilham Satria Putra ◽  
Stephanus Satria Waskitha ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Aldol Condensation ◽  
Antimalarial Activity ◽  
Docking Study ◽  
Docking Studies ◽  
Curcumin Analog ◽  
Molecular Docking Study ◽  
Antimalarial Agents ◽  
Curcumin Analogs ◽  
Ic50 Value

This research involves the synthesis, antimalarial evaluation, and molecular docking of several curcumin analogs. A total of six curcumin analog compounds were synthesized using aldol condensation using hydrochloric acid and sodium hydroxide catalysts. The synthesized compounds were elucidated using FTIR, 1H-NMR, 13C-NMR, and LC-MS/MS. Subsequently, all curcumin analogs were tested as an antimalarial agent against Plasmodium falciparum 3D7 strain, and their mechanism of action was evaluated through a molecular docking study. Six curcumin analogs, i.e. 2,6-bis(2-hydroxybenzylidene)cyclohexanone; 2,6-bis(2-hydroxybenzylidene)cyclopentanone; 1.5-bis(2-hydroxyphenyl)penta-1,4-diene-3-one; 2,6-bis(3-hydroxybenzylidene)cyclo-hexanone; 2,6-bis(3-hydroxybenzylidene)cyclopentanone; and 1,5-bis(3-hydroxy-phenyl)penta-1,4-diene-3-one have been successfully synthesized. In addition, 2,6-bis(2-hydroxybenzylidene) cyclopentanone demonstrated the lowest IC50 value and binding affinity of 0.04 µM and -7.6 kcal/mol, respectively. Based on molecular docking studies, this compound also showed the most potent antimalarial activity targeted at PfATP6.

Three-dimensional Quantitative Structure-activity Relationship (3DQSAR) and Molecular Docking Study of 2-((pyridin-3-yloxy)methyl) Piperazines as α7 Nicotinic Acetylcholine Receptor Modulators for the Treatment of Inflammatory Disorders

2020 ◽  
Vol 20 (11) ◽  
pp. 1031-1041
Author(s):  
Deepika Purohit ◽  
Vandana Saini ◽  
Sanjiv Kumar ◽  
Ajit Kumar ◽  
Balasubramanian Narasimhan
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
3D Qsar ◽  
Docking Study ◽  
Field Analysis ◽  
Receptor Protein ◽  
Molecular Docking Study ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Comfa Model

Background & Objective: Comparative molecular field analysis (CoMFA) of 27 analogues of 2-((pyridin-3-yloxy)methyl)piperazine derivatives was carried out using software Tripos SYBYL X. Optimal r2 (0.854) and q2 (0.541) values were obtained for the developed 3D-QSAR model. The contour plots obtained from CoMFA analysis have shown 13.84% steric contribution and 66.14% electrostatic contribution towards an anti-inflammatory activity. Methods: The homology model of the receptor protein, α7 nicotinic acetylcholine, was generated in SWISS MODELLER using auto template mode and was analysed for the quality using Procheck, QMEAN Z-score, Anolea and GROMOS plots. The QMEAN score for the model was observed to be - 3.862. The generated model of alpha 7 nicotinic acetylcholine receptor was used for docking study of 27 piperazine analogues using Auto-Dock 4.2.5.1. Results: The dock score obtained from docking analysis was then correlated with experimental pIC50 values for in-silico validation of the developed CoMFA model and a good correlation was obtained with correlation coefficient (r2) value of -0.7378. Conclusion: The present investigation suggests an optimal 3D-QSAR with CoMFA model for further evaluating new chemical entities based on piperazine skeleton.

3D QSAR Based Virtual Screening of Pyrido[1,2-a] Benzimidazoles as Potent Antimalarial Agents

2019 ◽  
Vol 16 (3) ◽  
pp. 301-312
Author(s):  
Kalicharan Sharma ◽  
Apeksha Srivastava ◽  
Pooja Tiwari ◽  
Shweta Sharma ◽  
Mohammad Shaquiquzzaman ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Antimalarial Activity ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Qsar Model ◽  
Docking Studies ◽  
Activity Data ◽  
Qsar Studies ◽  
Antimalarial Agents ◽  
Fisher Ratio

Background: Development of novel antimalarial agents has been one of the sought areas in medicinal chemistry. In this study the same was done by virtual screening of in-house database on developed QSAR model. </P><P> Methods: A six point pharmacophore model was generated (AADHRR.56) from 41 compounds using PHASE module of Schrodinger software and used for pharmacophore based search. Docking studies of the obtained hits were performed using GLIDE. Most promising hit was synthesized & biologically evaluated for antimalarial activity. </P><P> Result: The best generated model was found to be statistically significant as it had a high correlation coefficient r2= 0.989 and q2 =0.76 at 3 component PLS factor. The significance of hypothesis was also confirmed by high Fisher ratio (F = 675.1) and RMSE of 0.2745. The model developed had good predicted coefficient (Pearson R = 0.8826). The virtual screening on this model resulted in six hits, which were docked against FP-2 enzyme. The synthesized compound displayed IC50 value of 0.27&#181;g/ml against CQS (3D7) and 0.57μg/ml against CQR (RKL9). </P><P> Conclusion: 3D QSAR studies reviled that hydrophobic groups are important for anti-malarial activity while H-donor is less desirable for the same. Electron withdrawing groups at R1 position favours the activity. The biological activity data of the synthesized hit proved that the pharmacophore hypothesis developed could be utilized for developing novel anti-malarial drugs.

QSAR Studies on Thiazole Derivatives as HCV NS5A Inhibitors via CoMFA and CoMSIA Methods

2019 ◽  
Vol 16 (4) ◽  
pp. 453-460 ◽  
Author(s):  
Jiayu Li ◽  
Wenyue Tian ◽  
Diaohui Gao ◽  
Yuying Li ◽  
Yiqun Chang ◽  
...  
Keyword(s):  
Nonstructural Protein ◽  
External Validation ◽  
Three Dimensional ◽  
3D Qsar ◽  
Quantitative Structure Activity Relationship ◽  
Field Analysis ◽  
Thiazole Derivatives ◽  
Hydrogen Bond Acceptor ◽  
Qsar Studies ◽  
Comfa Model

Background: Hepatitis C Virus (HCV) infection is the major cause of hepatitis after transfusion. And HCV Nonstructural Protein 5A (NS5A) inhibitors have become a new hotspot in the study of HCV inhibitors due to their strong antiviral activity, rapid speed of viral removing and broad antiviral spectrum. Methods: Forty-five NS5A inhibitors were chosen to process three-dimensional quantitative structure- activity relationship (3D-QSAR) by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. A training set consisting of 30 compounds was applied to establish the models and a test set consisting of 15 compounds was applied to do the external validation. Results: The CoMFA model predicted a q2 value of 0.607 and an r2 value of 0.934. And the CoMSIA model predicted a q2 value of 0.516 and an r2 value of 0.960 established on the effects of steric, electrostatic, hydrophobic and hydrogen-bond acceptor. 0.713 and 0.939 were the predictive correlation co-efficients (r2pred) of CoMFA and CoMSIA models, respectively. Conclusion: These conclusions provide a theoretical basis for drug design and screening of HCV NS5A complex inhibitors.

Structural Insights into the Active Site of Human Sodium Dependent Glucose Co-Transporter 2: Homology Modelling, Molecular Docking, and 3D - QSAR Studies

2012 ◽  
Vol 65 (9) ◽  
pp. 1314 ◽  
Author(s):  
Srinivas Nakka ◽  
Lalitha Guruprasad
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Least Squares Method ◽  
Homology Modelling ◽  
3D Qsar ◽  
Field Analysis ◽  
Molecular Field ◽  
Relationship Analysis ◽  
Sodium Dependent ◽  
Structural Insights

Human sodium dependent glucose co-transporter 2 (hSGLT2) is a target for diabetes mellitus type 2 (T2DM). The 3D (three dimensional) homology model of hSGLT2 comprising 14 transmembrane helical domains was constructed and molecular docking of the inhibitors, C-aryl glucoside analogues, into the active site was studied. The 3D-QSAR (quantitative structure activity relationship) analysis was carried out on 43 C-aryl glucoside analogues as a training set. The molecular field analysis (MFA) with G/PLS (genetic partial least-squares) method was used to generate statistically significant 3D-QSAR (r2 = 0.857) based on a molecular field generated using electrostatic and steric probes. The QSAR model was validated using leave-one-out cross-validation, bootstrapping, and randomisation methods, and finally with an external test set comprising 10 inhibitors. The molecular docking studies provide structural insights into the active site and key interactions involved in the binding of inhibitors to hSGLT2 and these results corroborate with the 3D-QSAR analysis that provide the active conformation of inhibitors and the nature of interactive fields important for activity.

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.

Design, Synthesis, Antimalarial Activity and Docking Study of 7-Chloro-4- (2-(substituted benzylidene)hydrazineyl)quinolines

2020 ◽  
Vol 16 (7) ◽  
pp. 928-937 ◽  
Author(s):  
Jahnabi Kalita ◽  
Dipak Chetia ◽  
Mithun Rudrapal
Keyword(s):  
Antimalarial Drug ◽  
Disease Burden ◽  
Antimalarial Activity ◽  
Docking Study ◽  
Molecular Scaffold ◽  
Design Synthesis ◽  
Antimalarial Agents ◽  
Drug Molecules ◽  
Resistant Strains

Background: Malaria is a growing infectious disease burden due to the increasing emergence of resistant strains of Plasmodium falciparum. Because of the limited therapeutic efficacy of available antimalarial drugs, the development of potent antimalarial drug agents is therefore an urgent requirement to fight against resistant malaria. Objective: The objective of this work was to develop novel quinoline-baed antimalarial agents that would be active against resistant P. falciparum malaria. Methods: Some 7-chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines were synthesized for the evaluation of their potential as possible antimalarial agents, particularly against resistant malaria. The antimalarial activity of synthesized compounds was evaluated in vitro against bloodstage parasites of P. falciparum. Further, molecular docking and drug-likeness including ADMET (Absorption, Distribution, Metabolism, Elimination and Toxicity) studies were also carried out using in silico tools. Results: Results reveal the in vitro antimalarial activity of synthesized 7-chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines against P. falciparum. The docking study investigates the antimalarial effectiveness of synthesized quinolines as novel plasmepsin 2 inhibitors. Drug-likeness prediction exhibits acceptable drug-likeness and ADMET properties. Conclusion: Based upon our findings, it is concluded that the molecular scaffold of 7-chloro-4-(2- (substituted benzylidene)hydrazineyl)quinolines may be used as a lead structure for further modifications in the search of more potent antimalarial drug molecules.

Multi-targeted design and development of dihydroisoquinolines as potent antimalarial

2019 ◽  
Vol 15 ◽  
Author(s):  
Raviraj V. Mule ◽  
Sneha P. Rochlani ◽  
Prafulla B. Choudhari ◽  
Rakesh P Dhavale ◽  
Manish S. Bhatia
Keyword(s):  
Multidrug Resistance ◽  
Drug Design ◽  
Cysteine Protease ◽  
Antimalarial Activity ◽  
Docking Study ◽  
Hydrogen Binding ◽  
Design And Development ◽  
Binding Interaction ◽  
Structure Based Drug Design ◽  
Antimalarial Agents

Background: Cysteine protease and DHODH enzyme were identified as potential target and for synthesized compound which revealed binding interaction and confirmation from docking study. Development of new lead which specifically targeting cysteine protease and DHODH enzyme can be able to reduce the side effect and to overcome multidrug resistance. Objectives: Design and development of antimalarial agents by targeting cysteine protease and DHODH (Dihydroorotate dehydrogenase) enzyme by structure based drug design. Materials and Methods: In present work, rational development of antimalarial agents by targeting cysteine protease and DHODH has been done by integrating binding confirmation from virtual analysis and synthetic procedures. Result: A novel series of dihydroisoquinolines were designed by structure based drug design. Large compounds of dataset were screened for molecular docking study and subsequently all molecules were screened for drug like properties and toxicity study prior to synthesis. The designed molecules which analysed by virtual screening were synthesized, characterized and finally screened for antimalarial activity by performing bioassay. Synthesized compounds were showed greater antimalarial activity in terms percent inhibition. Conclusion: In this work, compound A1,A5,A6,A9 showed desirable inhibitory activity toward targets in terms of percentage and also specific hydrogen binding interaction with those targets. Further optimization in leads able to yield drug like candidate and it may able to overcome multidrug resistance.

Non-Nucleoside HIV-1 Reverse Transcriptase Inhibition Activity of a Series of Dihydroalkoxybenzyloxopyrimidine (DABO) Derivatives: CoMFA, CoMSIA and Docking Studies

2020 ◽  
Vol 5 (3) ◽  
pp. 265-272
Author(s):  
Bikash Kumar Sarkar ◽  
Ananda Sarkar ◽  
Atish Dipankar Jana
Keyword(s):  
3D Qsar ◽  
Docking Study ◽  
Binding Pocket ◽  
Qsar Model ◽  
Docking Studies ◽  
Field Analysis ◽  
Qsar Studies ◽  
3D Space ◽  
Pyrimidine Moiety ◽  
Hiv 1

CoMFA, CoMSIA and molecular docking studies have been carried out for a set of 42 dihydroalkoxybenzyloxopyrimidine (DABO) derivatives for which anti-HIV activity values are available. In 3D-QSAR studies-comparative molecular field analysis (CoMFA) as well as comparative molecular similarity indices analysis (CoMSIA) have been performed. Both the QSAR model nicely explains the inhibitory activities of DABO derivatives as well as provides molecular level insights revealing which regions in 3D space around the molecules are more important for their anti HIVactivities. These models have a quite high square correlation coefficient (r2 = 0.817 for CoMFA and r2 = 0.943 for CoMSIA). A docking study of the highest active molecule into the binding site of the protein HIV-1 RT (PDB ID-1RT1) shows that hydrogen bonding between pyrimidine moiety of the ligand and the Lysine-101 moiety along with Valine-106 moiety of the HIV protein play most important role for stabilizing the ligand in the binding pocket of the protein.

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