QSAR Studies Research Articles

Design and Synthesis of N-Substituted 3,4-Pyrroledicarboximides as Potential Anti-Inflammatory Agents.

In the present paper, we describe the biological activity of the newly designed and synthesized series N-substituted 3,4-pyrroledicarboximides 2a–2p. The compounds 2a–2p were obtained in good yields by one-pot, three-component condensation of pyrrolo[3,4-c]pyrrole scaffold (1a–c) with secondary amines and an excess of formaldehyde solution in C2H5OH. The structural properties of the compounds were characterized by 1H NMR, 13C NMR FT-IR, MS, and elemental analysis. Moreover, single crystal X-ray diffraction has been recorded for compound 2h. The colorimetric inhibitor screening assay was used to obtain their potencies to inhibit COX-1 and COX-2 enzymes. According to the results, all of the tested compounds inhibited the activity of COX-1 and COX-2. Theoretical modeling was also applied to describe the binding properties of compounds towards COX-1 and COX-2 cyclooxygenase isoform. The data were supported by QSAR study.

Catalytic synthesis, ADMET, QSAR and molecular modeling studies of novel chalcone derivatives as highly potent antioxidant agents

A series of (E)-3-(3-(5-chlorothiophen-2-yl)-1-(furan-2-carbonyl)-2,3-dihydro-1H-pyrazol-4-yl)-1-(substituted)prop-2-en-1-one derivatives (5a-c)) was synthesised from the reaction of 3-(5-chlorothiophen-2-yl)-1-(furan-2-carbonyl)-2,3-dihydro-1H-pyrazole-4-carbaldehyde (2) with various substituted acetophenes by the use of TiO2-ZnS in ethanol under reflux conditions. All are structurally supported by IR spectrum and the basic testing and screening, and find that compounds 5a are potential antioxidants for their in vitro-antioxidant activity against DPPH. The results in vitro were compared with the results of the molecular docking, ADMET, QSAR and bioactivity study and it was found that the results were observed in good correlations with in vitro anti-oxidant results in silicon binding affinities. The analysis of molecular dockings revealed the interactions between the synthesised ligands and protein tyrosine kinase (2HCK) amino acid residues and has a strong hydrogen connexion to this enzyme.

Radioprotectors: Nature's Boon.

Major approach in controlling as well as eradicating the cancerous growth is through radiotherapy, but this treatment leads to toxicity in the normal cells, leading to secondary malignancies, teratogenesis, and necrosis. More than 15,000 malignancies occur due to exposure to harmful radiations during computed tomography scans. Natural products are non-toxic; there have been reports that herbal products, when given along with radiation, have shown increased tumor control property. The discussed agents in this review have potential antioxidant, immunomodulatory, free radical scavenging, metal chelating, and anti-inflammatory properties. To reduce the chances of toxicity, reduction in radiation dose or reducing the frequency of the therapy is made which usually leads to a therapeutically poor outcome. The most feasible method is to protect the normal cells by administration of radioprotective agents either before or after the exposure. These agents have been tested on animals and human cell models for evaluating their safety window and toxicity profile at the cellular level. The study aims to compile the effective natural radioprotective agents available, which can be further exploited by using certain QSAR studies to increase their potency. Structured literature search from EMBASE, PubMed, Bentham Science, Scopus, and ScienceDirect was carried out and appropriate peer-reviewed review articles, as well as certain research articles, were included and compiled in this review paper. As various studies have indicated the harmful effects of ionizing radiations on normal cells, to reduce these effects, radioprotective agents are used before or after exposure to radiations. Compounds derived from natural sources are proved to have few side effects and they possess radioprotective property due to the presence of alkaloids, resins, volatile oils, tannins in their molecular structure. Various plants having such radioprotective constitutes have been identified for their radioprotective action and compiled in the present study.

Anthelmintic efficacy of natural saponins against Gyrodactylus kobayashii in goldfish (Carassius auratus) and their 3D-QSAR analysis.

Gyrodactylus spp. are common monogenean ectoparasites that may lead to significant fish mortality. To find effective anthelmintic agents with lower toxicity, a series of natural saponins were obtained and evaluated for their anthelmintic activity against Gyrodactylus kobayashii and acute toxicity to goldfish (Carassius auratus). Among all tested compounds, six compounds (1, 2, 3, 8, 10, and 13) shown higher anthelmintic activity and safety than widely used formaldehyde-based parasiticides, especially compound 1 having 100% anthelmintic efficacy against G. kobayashii at 0.3mg/L and a therapeutic index of 16.6. Also, the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of these saponins have been performed to explore the structural features reasonable for the anthelmintic activity against G. kobayashii. These models demonstrated that the hydroxyl group at C-17 position and the sugar moieties at C-3 position, especially the hydroxyl groups of the sugar moieties, were critical to the anthelmintic activity. The QSAR studies could provide useful information for further rational design and optimization of novel saponins for the control of gyrodactylosis.

Graph entropies of porous graphene using topological indices

The numerical values which play a significant role in QSAR and QSPR studies are topological indices. Out of many existing topological indices, the fundamental type of such indices depend on Shannon’s entropy measures that characterizes the graphs by analysing the structural information of graphs and networks. The graph entropy measures take part in various problem domains such as graph theory, biology and chemistry. Here, the chemical graph of porous graphene of graphite structure is discussed. Several degree-based topological indices are computed using definitions viz., First Zagreb, Second Zagreb, Randic, Reciprocal Randic, Atom-bond connectivity, Geometric arithmetic, Harmonic, Sum-connectivity, ABC4 and GA5 indices. Using the calculated values of topological indices, degree and edge weighted entropy of graph, the entropy measures are calculated viz., First Zagreb entropy, Second Zagreb entropy, Randic entropy, Reciprocal Randic entropy, Atom-bond connectivity entropy, Geometric arithmetic entropy, Harmonic entropy, Sum-connectivity entropy, ABC4 entropy and GA5 entropy for the porous graphene structure.

QSAR analysis of the acetylcholinesterase inhibitory activity of some tertiary amine derivatives of cinnamic acid

Acetylcholinesterase (AChE) is an essential enzyme in the nervous system that increases the rate of the hydrolysis of the neurotransmitter acetylcholine. Excessive hydrolysis of acetylcholine is one of the factors that cause Alzheimer’s disease, and the inhibition of AChE might be one way to prevent and control the disease. In the present study, a QSAR study was developed on a set of 72 tertiary amine derivatives of cinnamic acids as a new family of acetylcholinesterase inhibitors. Enhanced replacement method (ERM) was used for variable selection, and multiple linear regression (MLR) was performed to correlate between structural features of molecules and their acetylcholinesterase inhibitory activity. The result suggests that the four variables, namely, HVcpx, VEA2, HATS5u, and qpmax indices, play an important role in the AChE inhibitory activities. The proposed model exhibited good statistical parameters for the training set (with R2train = 0.913, q2LOO = 0.896, F-ratio = 140.04) and test set (R2test = 0.856, $$ {r}_m^2 $$ =0.79, $$ {r}_m^{\prime 2}=0.66 $$ , $$ \overline{r_m^2}=0.72 $$ , and $$ {\Delta r}_m^2=0.13 $$ ).

Synthesis and crystal structure of phosphonic acid and bisphosphoramidate derivatives: QSAR studies of their anti-fungal potential on Macrophomina Phaseolina (Tassi) Goid

A series of phosphonic acid and bisphosphoramidate derivatives were synthesized and characterized. The bioactivities against the fungal pathogen Macrophomina phaseolina and human acetylcholinesterase AChE enzyme were studied using QSAR based on multiple linear regression. L17, with (p-Cl–C6H4–NH) (p-Cl–C6H4)C(H)P(O)(OC2H5)2 skeleton, demonstrated a great mortality on the M. phaseolina mycelial growth by 83% inhibition at 150 mg/L; the other tested derivative showed moderate to weak antifungal activity against the fungus. QSAR model based on the GA-MLR method revealed the importance of 3D descriptors (De, Mor18e, H8m, and Mor30p) on the antifungal activity. It showed good capability in predicting the fungicidal activity of the studied molecules. Another derivative, L5, with (m-CH3–NC5H4–NH)(m-CH3–C6H4)C(H)P(O)(OCH3)2 skeleton displays the most potent anti-AChE activity. The electronic parameters, ΔEL-H, and ELUMO, have the highest contribution of human AChE. The authors suggest that these models could be usefully employed in designing more effective crop protection compounds without side effects on non-target organisms.

Theoretical Bioevaluation of 1,2,4-Thiadiazole-1,2,4-triazole Derivatives via Molecular Modelling Approach

Breast cancer still remains one of the precarious ailments among humans globally. The vulnerability of this ailment in homeopathic world remains colossal and this has drawn the attention of seasoned researchers to find lasting solution to this hazard. Therefore, 10 novel 1,2,4-thiadiazole-1,2,4-triazole derivatives were studied so as to explore their anti-breast cancer activities. The studied compounds were optimized using Spartan 14 and the QSAR study was executed by using Gretl and MATLAB. Also, docking study was observed using Pymol (for treating downloaded protein), Autodock Tool (for locating binding site in the downloaded protein and for converting ligand and receptor to .pdbqt format from .pdb format), Auto dock vina (for docking calculation) and discovery studio (for viewing the nonbonding interaction between the docked complexes). The selected descriptors were used to developed effective QSAR model and it was observed that the developed QSAR model using artificial neural network (ANN) predicted better than the prediction made by multiple linear regression (MLR). More so, the calculated binding affinity revealed that compound g (-11.4 kcal/mol) possess ability to inhibit 3α-hydroxysteroid dehydrogenase type 3 (PDB ID: 4xo6) than other studied compounds as well as etoposide (Standard).

Theoretical, Monte Carlo Simulations and QSAR Studies on Some Triazole Derivatives as Corrosion Inhibitors for Mild Steel in 1 M HCl

Theoretical, Monte Carlo Simulations and QSAR Studies on Some Triazole Derivatives as Corrosion Inhibitors for Mild Steel in 1 M HCl

Structural, QSAR, machine learning and molecular docking studies of 5-thiophen-2-yl pyrazole derivatives as potent and selective cannabinoid-1 receptor antagonists

We performed a structural study followed by theoretical analysis of the chemical descriptors and biological activity of a series of 5-thiophen-2-yl pyrazole derivatives as potent and selective cannabinoid-1 (CB1) receptor antagonists.

Detection of Natural Inhibitors against Human Liver Cancer Cell Lines through QSAR, Molecular Docking and ADMET Studies

Bentham Science - STM publisher of online and print journals, and related print/online book series. Bentham Science answers the information needs of scientists in the fields of pharmaceutical, biomedical, medical, engineering, technology, computer and social sciences.

On symmetric division deg index of trees with given parameters

Recently, the symmetric division deg ($ SDD $) index is proven to be a potentially useful molecular descriptor in QSAR and QSPR (quantitative structure-activity and structure-property relationships) studies. And its predictive capability is better than that of some popular topological indices, such as the famous geometric-arithmetic index and the second Zagreb index. In this work, the maximum $ SDD $ indices of trees with given matching number or domination number or independence number or number of pendant vertices or segments or diameter or radius are presented. Furthermore, the corresponding extremal trees are identified.

Molecular Insights of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole as CRF-1 Receptor Antagonists: Combined QSAR, Glide Docking, Molecular Dynamics, and In-silico ADME Studies.

Stress-dependent disorders cause severe harm to human health and trigger the risk of neurodegenerative disorder. Corticotropin-releasing factor-1 receptor was found to be a potent drug target.We evaluate the essential structural residues for pharmacophore identification through 2D and 3D QSAR analysis and identify the binding residues for a possible mechanism of CRF-1 binding with 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole derivatives through molecular docking and molecular dynamics simulations. The best 2D QSAR model was obtained through the MLR method with an r2 value of 0.8039 and a q2 value of 0.6311. Also,a 3D QSAR model was generated through the KNN MFA method with a q2 value of 0.6013 and a q2_se value of 0.3167. Further, docking analysis revealed that residue Glu196 and Lys334 were involved in hydrogen bonding and Trp9 in Π- Π stacking. Simulation analysis proves that target protein interactions with ligands were stable, and changes were acceptable for small and globular proteins. Compound B18, a benzimidazole derivative, has an excellent binding affinity towards CRF-1 protein compared to reference molecules; hence, this compound could be a potential drug candidate for stress-dependent disorders. Based on findings, 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole derivatives could be a novel class of corticotropin-releasing factor 1 receptor antagonists for stress-related disorders. All benzimidazole derivatives were found to be within the acceptable range of physicochemical properties. Hence, these observations could provide valuable information for the design and development of novel and potent CRF-1 receptor antagonists.

Synthesis, Biological Evaluation, Molecular Docking, ADME Predictions and QSAR Studies of Novel 1,2-Diazet and Pyrrole Derivatives as Anti-Inflammatory Agents

Synthesis, Biological Evaluation, Molecular Docking, ADME Predictions and QSAR Studies of Novel 1,2-Diazet and Pyrrole Derivatives as Anti-Inflammatory Agents

Thiopyrimidine‐5‐carbonitrile Derivatives as VEGFR‐2 Inhibitors: Synthesis, Anticancer Evaluation, Molecular Docking, ADME Predictions and QSAR Studies

AbstractIn this study, several novel thiopyrimidine‐5‐carbonitrile derivatives were synthesized and antitumor activity was investigated. Among them, N‐(4‐bromophenyl)‐2‐cyanoacetyl hydrazine‐1‐carbothioamide 6 revealed that the most potent cytotoxic activity against all tested cell lines, that it is why; it was subjected to in vitro kinase inhibitory assay. Molecular docking simulation was done to verify the binding mode towards VEGFR‐2 and afforded clear evidence on the observed anticancer behavior. Prediction of ADME properties and QSAR study of compounds was carried out, respectively.

3D QSAR studies on amphiphilic indoles for antimycobacterial activity

A persistent infection prolongs treatment duration and also enhances the chance of resistance development against antibiotics. Recently, a class of amphiphilic indole derivatives was discovered exhibiting bactericidal activity against both growing and nongrowing Mycobacterium bovis BCG (M. bovis BCG). These antibacterials are suggested to disturb the integrity and functioning of the cell membrane, a property that can help eradicate persistent organisms. This study article describes field-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of 79 amphiphilic indole derivatives. The aim of this QSAR study is to optimize this class of compounds for the development of more potent antimycobacterial agents. The results obtained indicate that steric interactions are crucial for antimycobacterial activity, while hydrogen bond donor groups participate negligibly in activity. The derived 3D-QSAR models showed acceptable r2 (0.91) and q2 (0.91) with aroot mean squared error (RMSE) of 0.08. The models were cross-validated using the leave-one-out method. Applying the same QSAR model to another congeneric series of amphiphilic indoles externally validated the QSAR model. The model could appreciably predict the activity (pMIC50 ) of this congeneric series of amphiphilic indoles, with an RMSE of 0.49, indicating the robustness of the model and its efficiency in predicting the potentially active compounds.

Discovery of Novel Coumarin Analogs against the α-Glucosidase Protein Target of Diabetes Mellitus: Pharmacophore-Based QSAR, Docking, and Molecular Dynamics Simulation Studies

Diabetes mellitus (DM) is a chronic metabolic disease, the third killer of mankind. The finding of potent drugs against diabetes remains challenging. In the present study, coumarin derivatives with known biological activity against diabetic protein have been used to predict functional groups’ positions on coumarin derivatives. α-Glucosidase is a brush border membrane-bound lysosomal enzyme from the hydrolase enzyme family. It plays an important role in the metabolism of glycoproteins. Inhibitors of lysosomal α-glucosidase can reduce postprandial hyperglycemia. Due to this, lysosomal α-glucosidase is a good therapeutic target for drugs. A total of 116 coumarin derivatives with IC50 values against lysosomal α-glucosidase were selected for a CADD (computer-aided drug design) approach to identify more potent drugs. Pharmacophore modeling and atom-based 3-QSAR of 116 active compounds against lysosomal α-glucosidase were performed and identified positions and types of groups to increase activity. We performed molecular docking of 116 coumarin derivatives against the lysosomal α-glucosidase enzyme, and three compounds (isorutarine, 10_, and 36) resulted in a docking score of −7.64, −7.12, and −6.86 kcal/mol. The molecular dynamics simulation of the above three molecules and protein complex performed for 100 ns supported the interaction stability of isorutarine, 10_, and 36 with the lysosomal binding site α-glucosidase.

Detection of Natural Inhibitors against Human Liver Cancer Cell Lines through QSAR, Molecular Docking and ADMET Studies.

Liver cancer is ranked as the fifth most prevalent and third most lethal cancer worldwide. The incidence rates of this cancer are on the rise, and only limited treatment options are available. To identify and optimize the inhibitors of liver cancer cell-lines, a QSAR model was developed by using multiple linear regression methods. The robustness of the model was validated through statistical methods and wet-lab experiments. The developed QSAR models yielded high activity descriptor relationship accuracy of 91%, referred to by regression coefficient (r2= 0.91), and a high activity prediction accuracy of 89%. The external predicted (pred_r2) ability of the model was found to be 90%. The QSAR study indicates that chemical descriptors such as to measure of electronegative atom count (Epsilon3), atom type count descriptors (MMFF_10), number of a carbon atom connected with four single bonds (SssssCE- index), molecular weight and, number of oxygen atom connected with two aromatic bonds (SaaOE-index) are significantly correlated with anticancer activity. The model, which was validated statistically and through wet-lab experiments, was further used in the virtual screening of potential inhibitors against the liver cancer cell line WRL68. ADMET risk screening, synthetic accessibility, and Lipinski's rule of five are used to filter false positive hits. AfterwardS, to achieve a set of aligned ligand poses and rank the predicted active compounds, docking studies were carried out. The studied compounds and their metabolites were also analyzed for different pharmacokinetics parameters. Finally, a series of compounds was proposed as anticancer agents.

Retracted: DFT Based QSAR Study of Enzyme Ribonucleoside Diphosphate Reductase

Retracted: DFT Based QSAR Study of Enzyme Ribonucleoside Diphosphate Reductase

Rational in silico drug design of HIV-RT inhibitors through G-QSAR and molecular docking study of 4-arylthio and 4-aryloxy-3-iodopyridine-2(1-H)-one derivative

BackgroundHuman immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV). Antiretroviral therapy (ART) against HIV infection offers the promise of controlling disease progression and prolonging the survival of HIV-infected patients. Reverse transcriptase (RT) inhibitors remain the cornerstone of the drug regimen to treat AIDS. In this direction, by using group-based QSAR study (G-QSAR), identification of the structural need for the development of lead structure with reverse transcriptase inhibition on 97 reported structures was carried out. Docking analysis was performed further and suggested the structural properties required for binding affinity with the receptor. The molecules in the data set were fragmented into six (R1, R2, R3, R4, R5, and R6) by applying the fragmentation pattern. Three G-QSAR models were selected based on the statistical significance of the model. The molecular docking study was performed to explain the structural properties required for the design of potent HIV-RT inhibitors.ResultsThe statistically validated QSAR models reveal the presence of higher hydrophobic groups containing single-bonded –Br atom, 2 aromatic bonded –NH group with less electronegativity, and entropic interaction fields at R2 essential for better anti-HIV activity. The presence of a lipophilic group at R3, oxygen and sulfur connected with two aromatic bonds at R4, and –CH3 group at R5 was fruitful for reverse transcriptase inhibition. Docking studies of the selected inhibitors with the active site of reverse transcriptase enzyme showed hydrogen bond, Van der Waal’s, charge, aromatic, and π–π interactions with residues present at the active site.ConclusionThe results of the generated models provide significant site-specific insight into the structural requirements for reverse transcriptase inhibition during the design and development of novel anti-HIV compounds. Molecular docking study revealed the binding interaction between the ligand and the receptor which gave insight towards the structure-based design for the discovery of more potent compounds with better activity against HIV infection.