2D-QSAR modeling,drug-likeness studies,ADMET prediction,and molecular docking for anti-lung cancer activity of 3-substituted-5-(phenylamino) indolone derivatives

Structural Chemistry - In this work, 2D-quantitative structure–activity relationship (QSAR) studies were performed on a set of 40 indolone derivative hybrids; the 40 indolone derivatives were...     

3D-QSAR,molecular docking and ADMET studies of thioquinazolinone derivatives against breast cancer

Breast cancer is a deadly disease and the second largest cause of mortality on a worldwide platform. Despite the availability of several cancer treatments, life expectancies stay relatively poor. Consequently, the medicinal chemistry community prioritizes the quick discovery of novel anticancer drugs. In recent years, computational approaches have been widely used to accelerate the drug development process. In light of this, in the current work, we performed three-dimensional quantitative structure-activity relationships (3D-QSAR) and molecular docking analyses on thioquinazolinone derivatives with aromatase enzyme (PDB: 3S7S). External validation was used to validate the prediction capabilities of the generated model. The best CoMSIA (comparative molecular similarity indices analysis) model exhibited the significant values of $Q^2$, $R^{2}and$ $R_{pred}^2$. These findings suggested that the electrostatic, hydrophobic and hydrogen bond donor and acceptor fields have a significant effect on inhibition of breast cancer. Thus, a number of innovative potent aromatase inhibitors were designed and their biological activities were predicted based on the best model. Furthermore, molecular docking studies were carried out for the designed compounds against breast cancer. Additionally, ADMET proprieties were used to evaluate drug-likeness of these novel drug candidates. The most active compounds found by these computational studies could be helpful for synthesis and testing as prospective future anti-cancer treatments.     

3D-QSAR,molecular docking and in silico ADMET studies of propiophenone derivatives with anti-HIV-1 protease activity

Structural Chemistry - HIV protease inhibitors are one of the most important agents for the treatment of HIV infection. In this work, molecular modeling studies combining 3D-QSAR, molecular...     

Synthesis,characterization of novel quinoline-2-carboxamide based chalcone derivatives and their molecular docking,photochemical studies

Abstract

Novel series of quinoline-2-carboxamide based chalcone derivatives (5a–g) have synthesized and characterized using ¹H-NMR, 13C-NMR, Mass, and elemental analysis. In-silico molecular docking studies exhibited that synthesized compounds 5a and 5g are good binding energy (?8.46?kcal and ?9.46?kcal) toward the essential requirements of targeted compounds for EGFR receptor-bearing quinazoline inhibitor (PDB ID: 1M17(Lapitinib)). UV-Vis and fluorescence spectroscopy measurements provided a significant effect on the absorption, emission cyclic voltammetry (CV), and highest occupied molecular orbital (HOMO). Lowest unoccupied molecular orbital (LUMO) values of compound 5g are also confirmed band along with intramolecular charge transfer character (D-π-A). The red shift maxima (510?nm) the emission spectra in various solvents with increasing solvent polarity.     

Quinoline conjugated 2-azetidinone derivatives as prospective anti-breast cancer agents: In vitro antiproliferative and anti-EGFR activities,molecular docking and in-silico drug likeliness studies

Two series [1–8 (series-1) and 9–16 (series-2)] of quinoline conjugated 2-azetidinones were evaluated for their antiproliferative potential against breast cancer cell lines MCF7 and MDA-MB-231 respectively. All the compounds were more active towards against MCF7 than MDA-MB-231 cancer cell lines and few compounds activity was more than the standard erlotinib. For instance, the compound 16 of series-2 bearing electron withdrawing fluorine atom at the 6th position of quinoline ring showed promising activity with MIC values of 2.33 ± 0.19 µg/mL for MCF7 and 4.19 ± 0.22 µg/mL for MDA-MB-231 cells, respectively. In a similar way, the compounds 8 and 14 containing fluorine and chlorine substituents respectively, and located at position-6 of quinoline scaffold showed better activity than erlotinib. The ability of target compounds to inhibit EGFR tyrosine kinase, one of the key enzymes involved in breast carcinomas was evaluated by in vitro enzymatic assay and it was found that the compound 8 had close inhibitory activity to erlotinib with an %inhibition of 97.1 ± 0.08 at 10 µM. The compounds showed selective toxicity on the cancer cell lines as their IC₅₀ values are high against the human normal liver cell line-LO2. Further, the docking studies of the promising compounds 8, 14 and 16 revealed the important molecular interactions with the EGFR kinase enzyme (PDB ID: 6S9B). The physicochemical and pharmacokinetic properties of the most active compounds were predicted using Swiss ADME and pkCSM tools respectively. The most promising compounds arisen from the present study can be considered as prospective lead molecules for anticancer activity against breast carcinoma.     

Spectroscopic,quantum chemical,ADMET and molecular docking studies of echinatin: a prospective tuberculosis drug

Research on Chemical Intermediates - Tuberculosis (TB) is a potentially fatal infectious illness affecting mostly the lungs. Tuberculosis bacteria are communicated from person to person via minute...     

Anti-cancer,anti-oxidant and molecular docking studies of thiosemicarbazone indole-based derivatives

Based on the structural elements of bioactive 3-substituted indoles, a new series of indole–thiosemicarbazone hybrid derivatives were designed, synthesized, and well-characterized using different spectral techniques. The intended scaffolds were screened for their in vitro anti-proliferative activities against breast cancer (MCF-7), lung cancer (A-549), and liver cancer (Hep-G2) cell lines, as well as their anti-oxidant properties. Cytotoxicity studies revealed that compound 6n was the most potent, at least threefold more potent than the commercially available reference drug etoposide, against A-549. In addition, morphological analysis by the acridine orange/ethidium bromide double staining test and flow cytometry analysis confirmed induction of apoptosis in the A-549 cells by compound 6n. In order to validate the experimental results, molecular studies were performed to achieve the possible binding interactions of the most potent compound (6n) and colchicine with tubulin as well as ANP with ATPase domain of topoisomerase IIα active sites. Moreover, the radical scavenging potential of the final derivatives was found to be excellent with the range of 0.015–0.630 µM, comparable to the standard ascorbic acid (0.655 µM).

     

New quinoxaline-piperazine-oxazole conjugates: Synthesis,in vitro anticancer,in silico ADMET,and molecular docking studies

In this paper, we describe the synthesis of some new quinoxaline-piperazine-oxazole amide conjugates 6a-n from 3-chloroquinoxaline-2-carbonitrile using well-known reaction sequences. The synthesized compounds were characterized by ¹H NMR,¹³C NMR, and mass spectral analysis. The compounds were tested for their in vitro antiproliferative activity toward four different cancer cell lines such as PC-3, MCF-7, DU-145, and A-549 by MTT method. The compounds, 6c, 6h, 6i , and 6n were found to be more potent than the standard Erlotinib. In vitro tyrosine kinase EGFR inhibition studies using four potent compounds revealed that 6n has double inhibiting tendency with value IC₅₀ of 0.22 μM and 6h with value of IC₅₀ 0.27 μM compared to reference compound. Molecular docking studies of active compounds, 6c , 6h , 6i , and 6n on EGFR receptor suggested that all the compounds have more binding energies than that of Erlotinib. Furthermore, the in silico pharmacokinetic profile was accomplished for the active compounds, 6c , 6h , 6i , and 6n using SWISS/ADME and pk CSM, whereas compounds, 6h , 6i , and 6c followed Lipinski rule, Veber rule, Egan rule and Muegge rule. The remaining compound 6n did not follow Lipinski rule, Ghose rule because one common violation, that is, because of high molecular weight (MW > 350).     

Novel oxadiazole functionalized pyridopyrimidine derivatives; their anticancer activity and molecular docking studies

A series of novel oxadiazole functionalized pyridopyrimidine derivatives prepared starting from 6-methyl/ethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile 1 . This compound 1 on reaction with sulfuric acid obtained compound 2 , further compound 2 on reaction with chloroacetamide followed by reaction with ethoxy methylene malonic diethyl ester coupling and further cyclization to obtain compound 5 . Compound 5 on reaction with hydrazide hydrate obtained hydrazide derivatives 6 . Compound 6 on reaction with diverse substituted aromatic acids to get oxadiazole derivatives 7a–l . All the final compounds 7a–l evaluated for anticancer activity against four human cancer cell lines such as HeLa—cervical cancer (CCL-2); COLO 205—colon cancer (CCL-222); HepG2—liver cancer (HB-8065); and MCF7—breast cancer (HTB-22) and promising compounds 7d and 7k have been identified and evaluated for molecular docking interactions.     

Synthesis of tetrahydroisoquinoline derivatives and evaluation of their anti-breast cancer activity

Four novel tetrahydroisoquinoline derivatives 1–4 were synthesized and characterized by IR, ¹H NMR, HRMS, and single crystal X-ray crystallography. Anticancer effect of the products were studied on five human breast cancer cell lines including MDA-MB-231, MDA-MB-468, SK-BR-3, MCF7, HCC70 T4-2. Compounds 3 and 4 demonstrated higher activity than 1 and 2.     

Bis coumarinyl bis triazolothiadiazinyl ethane derivatives: Synthesis,antiviral activity evaluation,and molecular docking studies

A series of novel 3,3′-(3,3′-(dihydroxy/hydroxyethane-1,2-diyl)bis(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6,3-diyl))bis(2H-chromen-2-ones) were prepared by the condensation of thiocarbohydrazide with tartaric acid or malic acid followed by various 3-(2-bromoacetyl)-2H-chromen-2-ones in two steps with good yields. All the synthesized compounds were characterized by analytical and spectral (IR, ¹H NMR, ¹³C NMR, and mass) data. These synthesized bis(triazolothiadiazinyl coumarin) compounds were evaluated for broad spectrum of antiviral activity. Among all the tested compounds, compound 5f exhibited antiviral activity against H1N1 virus. The molecular docking studies of these compounds against H1N1 neuraminidase enzyme were performed. The binding affinity and binding values were compared with standard drugs.     

One-pot,four-component synthesis of benzylpyrazolyl naphthoquinone derivatives and molecular docking studies

A highly efficient, green, one-pot, four-component approach for the synthesis of benzylpyrazolyl naphthoquinone derivatives (5a–p) have been developed by the domino reaction of 2-hydroxy naphthoquinone, aromatic aldehyde, ethyl acetoacetate, and phenyl hydrazine derivatives in water and employed p-toluene sulfonic acid (p-TSA) as the right choice of catalyst at reflux. Docking simulation was performed to position compounds 5a, 5b, and 5g into the anaplastic lymphoma kinase (ALK) structure active site to determine the probable binding model.     

Synthesis,biological evaluation and molecular docking studies of novel benzimidazole derivatives

A novel series of N-substituted-benzimidazolyl linked para substituted benzylidene based molecules containing three pharmacologically potent hydrogen bonding parts namely; 2,4-thiazolidinedione (TZD: a 2,4-dicarbonyl), diethyl malonate (DEM: a 1,3-diester and an isooxazolidinedione analog) and methyl acetoacetate (MAA: a β-ketoester) (6a–11b) were synthesized and evaluated for in vitro α-glucosidase inhibition. The structure of the novel synthesized compounds was confirmed through the spectral studies (LC–MS, ¹H NMR, ¹³C NMR, FT-IR). Comparative evaluation of these compounds revealed that the compound 9b showed maximum inhibitory potential against α-amylase and α-glucosidase giving an IC₅₀ value of 0.54 ± 0.01 μM. Furthermore, binding affinities in terms of G score values and hydrogen bond interactions between all the synthesized compounds and the AA residues in the active site of the protein (PDB code: 3TOP) to that of Acarbose (standard drug) were explored with the help of molecular docking studies. Compound 9b was considered as promising candidate of this series.     

QSAR,docking studies of 1,3-thiazinan-3-yl isonicotinamide derivatives for antitubercular activity

The enzyme – enoyl acyl carrier protein reductase (enoyl ACP reductase) is a validated target for antitubercular activity. Inhibition of this enzyme interferes with mycolic acid synthesis which is crucial for Mycobacterium tuberculosis cell growth. In the present work 2D and 3D quantitative structure activity relationship (QSAR) studies were carried out on a series of thiazinan–Isoniazid pharmacophore to design newer analogues. For 2D QSAR, the best statistical model was generated using SA-MLR method (r² = 0.958, q² = 0.922) while 3D QSAR model was derived using the SA KNN method (q² = 0.8498). These studies could guide the topological, electrostatic, steric, hydrophobic substitutions around the nucleus based on which the NCEs were designed. Furthermore, molecular docking was performed to gauze the binding affinity of the designed analogues for enoyl ACP reductase enzyme. Amongst all the designed analogues the binding energies of SKS 01 and SKS 05 were found to be −5.267 kcal/mol and −5.237 kcal/mol respectively which was comparable with the binding energy of the standard Isoniazid (−6.254 kcal/mol).     

Furanone derivatives as new inhibitors of CDC7 kinase: development of structure activity relationship model using 3D QSAR,molecular docking,and in silico ADMET

Cell division cycle 7 (CDC7) is a serine/threonine kinase, which plays a vital role in the replication initiation of DNA synthesis. Overexpression of the CDC7 in various tumor growths and in cell proliferation makes it a promising target for treatment of cancers. To investigate the binding between the CDC7 and furanone inhibitors, and in order to design highly potent inhibitors, a three-dimensional quantitative structure activity relationship (3D-QSAR) with molecular docking was performed. The optimum CoMSIA model showed significant statistical quality on all validation methods with a determination coefficient (R²?=?0.945), bootstrapping R² mean (BS-R²?=?0.960), and leave-one-out cross-validation (Q²) coefficient of 0.545. The predictability of this model was evaluated by external validation using a test set of nine compounds with a predicted determination coefficient R²_test of 0.96, besides the mean absolute error (MAE) of the test set was 0.258 log units. The extracted contour maps were used to identify the important regions, where the modification was necessary to design a new molecule with improved activity. Furthermore, a good consistency between the molecular docking and contour maps strongly demonstrates that the molecular modeling is reliable. Based on those obtained results, we designed several new potent CDC7 inhibitors, and their inhibitory activities were validated by the molecular models. Additionally, those newly designed inhibitors showed promising results in the preliminary in silico ADMET evaluations.     

Synthesis,anticancer activity and molecular docking studies of novel pyrido[1,2-a]pyrimidin-4-one derivatives

A series of novel triazolothione, thiadiazole, triazole, and oxadiazole-functionalized pyrido[1,2-a]pyrimidin-4-ones 6a–6l and 7a–7f were prepared, starting from pyridine derivatives 1a and 1b. All the compounds 6a–6l and 7a–7f were screened against four human cancer cell lines (HeLa, COLO205, Hep G2, and MCF 7), among which compounds 6d, 6h, 6j, 7b, and 7e showed promising anticancer activity. Molecular docking studies showed good binding energy and exhibited interactions and better lower free energy values, indicating more thermodynamically favored interaction.     

Combining molecular docking and molecular dynamics studies for modelling Staphylococcus aureus MurD inhibitory activity

The ATP-dependent bacterial MurD enzyme catalyses the formation of the peptide bond between cytoplasmic intermediate UDP-N-acetylmuramoyl-L-alanine and D-glutamic acid. This is essential for bacterial cell wall peptidoglycan synthesis in both Gram-positive and Gram-negative bacteria. MurD is recognized as an important target for the development of new antibacterial agents. In the present study we prepared the 3D-stucture of the catalytic pocket of the Staphylococcus aureus MurD enzyme by homology modelling. Extra-precision docking, binding free energy calculation by the MM–GBSA approach and a 40 ns molecular dynamics (MD) simulation of 2-thioxothiazolidin-4-one based inhibitor $1 was carried out to elucidate its inhibition potential for the S. aureus MurD enzyme. Molecular docking results showed that Lys19, Gly147, Tyr148, Lys328, Thr330 and Phe431 residues are responsible for the inhibitor–protein complex stabilization. Binding free energy calculation revealed electrostatic solvation and van der Waals energy components as major contributors for the inhibitor binding. The inhibitor-modelled S. aureus protein complex had a stable conformation in response to the atomic flexibility and interaction, when subjected to MD simulation at 40 ns in aqueous solution. We designed some molecules as potent inhibitors of S. aureus MurD, and to validate the stability of the designed molecule D1-modelled protein complex we performed a 20 ns MD simulation. Results obtained from this study can be utilized for the design of potent S. aureus MurD inhibitors.