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.

scholarly journals COMBINATORIAL PHARMACOPHORE MODELING AND ATOM BASED 3D QSAR STUDIES OF BENZOTHIADIAZINES AS HCV-NS5B INHIBITORS

2018 ◽  
Vol 10 (3) ◽  
pp. 43
Author(s):  
Prasanthi Polamreddy ◽  
Vinita Vishwakarma ◽  
Manoj Kumar Mahto
Keyword(s):  
Virtual Screening ◽  
Correlation Coefficient ◽  
Current Model ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Qsar Model ◽  
Pharmacophore Modeling ◽  
Structural Protein ◽  
Pearson's R ◽  
Pearson’S R

Objective: The objective of the current study was to elucidate the 3D pharmacophoric features of benzothiadiazine derivatives that are crucial for inhibiting Hepatitis C virus (HCV) Non-structural protein 5B (NS5B) and quantifying the features by building an atom based 3D quantitative structure-activity relationship (3D QSAR) model.Methods: Generation of QSAR model was carried out using PHASE 3.3.Results: A five-point pharmacophore model with two hydrogen bond acceptors, one negative ionization potential and two aromatic rings (AANRR) was found to be common among a maximum number of benzothiadiazine based NS5B inhibitors. A statistically significant 3D QSAR model was obtained from AANRR.6 which had correlation-coefficient (R2) value of 0.924, cross-validated correlation-coefficient (Q2) of 0.774, high Fisher ratio of 138 and low root mean square standard error (RMSE=0.29). There is another parameter, Pearson’s R, its value emphasizes correlation between predicted and observed activities of the test set. For the current model, Pearson’s R-value is 0.90, hence underlining the good quality of the model. The present study suggests that nitrogen atom of benzothiadiazine sulfamide ring, oxyacetamide group attached to C7 carbon of benzothiadiazine and sulfonamide oxygens are crucial for NS5B inhibitory activity. Prediction of activities of hit drugs generated in earlier research suggests that Aprepitant (Phase predicted activity: 6.9) could be a potential NS5B inhibitor.Conclusion: This 3D QSAR model developed was statistically good and can be used to predict the activities of newly designed NS5B inhibitors and virtual screening as well. Predict the activities of newly designed NS5B inhibitors and virtual screening as well.

scholarly journals The Integration of Pharmacophore-Based 3D QSAR Modeling and Virtual Screening in Identification of Natural Product Inhibitors against SARS-CoV-2

2020 ◽  
Author(s):  
Samira Norouzi ◽  
Maryam Farahani ◽  
Samad Nejad Ebrahimi
Keyword(s):  
Virtual Screening ◽  
3D Structure ◽  
3D Qsar ◽  
Qsar Model ◽  
Docking Studies ◽  
Molecular Characteristics ◽  
Qsar Modeling ◽  
Data Set ◽  
Public Health Emergencies ◽  
Current Outbreak

Background: The current outbreak of Coronavirus Disease 2019 (SARS-CoV-2) led to public health emergencies all over the world and made it a global concern. Also, the lack of an effective treatment to combat this virus is another concern that has appeared. Today, increasing knowledge of biological structures like increasing computer power brings about a chance to use computational methods efficiently in different phases of the drug discovery and development for helping solve this new global problem. Methods: In this study, 3D pharmacophores were generated based on thirty-one structures with functional affinity inhibition (antiviral drugs used for SARS and MERS) with IC50<250 µM from the literature data. A 3D-QSAR model has been developed and validated to be utilized in virtual screening. Results: The best pharmacophore models have been utilized as 3D queries for virtual screening to gain promising inhibitors from a data set of thousands of natural compounds retrieved from PubChem. The hit compounds were subsequently used for molecular docking studies to investigate their affinity to the 3D structure of the SARS-CoV-2 receptors. The ADMET properties calculate for the hits with high binding affinity. Conclusion: The study outcomes can help understand the molecular characteristics and mechanisms of the binding of hit compounds to SARS-CoV-2 receptors and promising identification inhibitors that are likely to be evolved into drugs.

Discovery of novel antimalarial drugs based on thiosemicarbazone derivatives: An in silico approach

2021 ◽  
Vol 16 ◽  
Author(s):  
Arjun Anant ◽  
Kamalpreet Kaur ◽  
Vivek Asati
Keyword(s):  
Amino Acids ◽  
Plasmodium Falciparum ◽  
Virtual Screening ◽  
Trichomonas Vaginalis ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Docking Studies ◽  
Qsar Study ◽  
Zinc Compounds ◽  
Qsar Analysis

Background: Thiosemicarbazones belongs to the group of semicarbazides which contains sulfur atom instead of the oxygen atom. Several studies have shown that they are effective against extracellular protozoans like Trichomonas vaginalis, Plasmodium falciparum, Trypanosoma cruzi and other parasites. Objective: The current research involves pharmacophore model design, 3-D-QSAR, virtual screening, and docking studies, all of which are evaluated using various parameters. Methods: The present study was performed by Schrodinger software. A total of 40 ligands were selected for the development of 3D QSAR models. To predict the pIC50 values in 3D-QSAR analysis, the entire dataset was divided into two sets, training and test sets, in a 7:3 ratio. The selected pharmacophore hypothesis has been selected for the virtual screening study. Results: DHHRR_1 emerged as the best pharmacophore model with a survival score of 5.80. The 3D QSAR study showed a significant model with R2 =0.91 and. Q2 = 0.73. The series top-scoring compound 7e had a docking score of -10.44 and showed interactions with the amino acids ARG-265, PHE-227, and LEU-531 required for activity. The developed pharmacophore model has been used for screening of ZINC compounds where ZINC26244107, ZINC13469100, ZINC01290725and ZINC01350173 showed thebest XP docking scores (-11.60, -11.27, -11.35, -10.52, consecutively) with binding important amino acids ARG265, HIE185 and LEU 531 against plasmodium falciparum, PDB ID: 5TBO. These results wereevaluated with thestandard antimalarial drug chloroquine. ADME analysis showed the drug-likeness properties of the compounds. Conclusion: The results of the present study may be helpful for the future development of antimalarial compounds against Plasmodium falciparum.

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.

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.

IN-SILICO STUDIES OF ANTI-PROLIFERATIVE CURCUMIN ANALOGS

2021 ◽  
pp. 24-26
Author(s):  
Monu Kumar Shukla
Keyword(s):  
In Silico ◽  
3D Qsar ◽  
Qsar Model ◽  
Physicochemical Characteristics ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Qsar Studies ◽  
Anticancer Properties ◽  
Curcumin Analogues ◽  
In Silico Studies

Prostate cancer affects males more than women. Curcumin, a bioactive component of turmeric, reported to have anticancer properties on several cancer cell lines. Researchers utilised molecular docking to generate new curcumin analogues, quantify their characteristics, and anticipate its mode of action. In this research article QSAR studies were performed on 40 curcumin analogues using V-life MDS 3.5 software. The physicochemical characteristics were computed using Molinspiration Cheminformatics software. The best QSAR model for 2D and 3D QSAR was selected. Then ten compounds were designed and improved based on model results directly linked to activity. The in-silico approach predicted the good biological activity of compounds. Docking studies were performed using Akt1 as a probable target. Among the developed compounds, MKS50 has the best docking score (-7.175 kcal/mol). This study will provide a new path for the design, synthesis, and biological evaluation of novel curcumin analogues.

Pharmacophore Based 3D-QSAR, Virtual Screening and Docking Studies on Novel Series of HDAC Inhibitors with Thiophen Linker as Anticancer Agents

2016 ◽  
Vol 19 (9) ◽  
pp. 735-751 ◽  
Author(s):  
Preeti Patel ◽  
Avineesh Singh ◽  
Vijay Patel ◽  
Deepak Jain ◽  
Ravichandran Veerasamy ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Anticancer Agents ◽  
Hdac Inhibitors ◽  
3D Qsar ◽  
Docking Studies

scholarly journals SYNTHESIS AND ANTIMALARIAL ACTIVITY OF SOME NEW 3-PHENYL-2-THIOXOTHIAZOLIDIN-4-ONE DERIVATIVES

2017 ◽  
Vol 9 (3) ◽  
pp. 58
Author(s):  
Mehul Zaveri ◽  
Neha Kawathekar
Keyword(s):  
Antimalarial Activity ◽  
Research Work ◽  
Aromatic Aldehydes ◽  
Maximum Activity ◽  
Spectroscopic Techniques ◽  
Activity Data ◽  
Antimalarial Agents ◽  
Ic50 Values ◽  
Current Therapies

Objective: Current therapies to treat P. falciparum malaria are heavily reliant on artemisinin-based combinations. However, resistance to artemisinin has recently been identified, and resistance to key artemisinin partner drugs is already widespread. Therefore, there is an urgent need for new antimalarial drugs with improved attributes over older therapies. The objective of this research work is to synthesize new antimalarial agents more effective against clinically relevant malarial strains.Methods: In present work, a series of ten 3-phenyl-2-thioxothiazolidin-4-one (MF1-MF10) derivatives, were synthesized by Knoevenagel condensation of N-phenyl rhodanine (I1) with substituted aromatic or hetro aromatic aldehydes using microwave irradiation. N-phenyl rhodanine (I1) was synthesized by a conventional reaction involving methyl-2-mercaptoacetate (1) and phenyl Isothiocyanates in presence of triethylamine. All the synthesized compounds were characterized by various spectroscopic techniques and evaluated for in-vitro antimalarial activity by microdilution technique against resistance strains of Plasmodium falciparum.Results: The antimalarial activity data showed that six compounds (MF1, MF3, MF4, MF5, MF7 and MF8) exhibited IC50 values ranging from 1.0-1.30 µg/ml, three compounds (MF2, MF6 and MF10) displayed IC50 values in the range of 0.9-1.0 µg/ml. Compound MF9 showed most significant result with maximum activity (IC50 = 0.85µg/ml).Conclusion: The antimalarial activity results revealed that compound MF9 possess potent activity and could be identified as a promising lead for further investigation.

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