Synthesis,anticancer activity and docking studies of pyrazoline and pyrimidine derivatives as potential epidermal growth factor receptor (EGFR) inhibitors

A search for anticancer agents has prompted the design and synthesis of new chalcone, pyrazoline and pyrimidine derivatives as potential epidermal growth factor receptor (EGFR) kinase inhibitors. These derivatives’ binding affinities were predicted by AutoDock, which showed that chalcone, pyrazoline and pyrimidine derivatives as EGFR-kinase inhibitors have good binding energies, ranging from ?10.91 to ?7.32 kcal/mol. These compounds were synthesized and characterized using elemental analysis (CHN analysis) and spectroscopic techniques (FTIR and NMR). Among the pyrazoline derivatives, 4Aiii has revealed a superior in vitro activity, inhibiting the EGFR kinase even at a low concentration of 0.19 μM compared to the pyrimidine derivative, 5Bii. In contrast, the cytotoxic effect of these derivatives was studied against hormonal and non-hormonal breast cancer cell lines. Most of the pyrazoline derivatives were able to express their cytotoxic effect efficiently against hormonal breast cancer but only one pyrimidine derivative managed to express its activity against hormonal breast cancer.     

Molecular stabilities,conformational analyses and molecular docking studies of benzimidazole derivatives bearing 1,2,4-triazole as EGFR inhibitors

Structural Chemistry - A detailed study of the tautomeric properties, the conformations, and the mechanism behind the anti-cancer properties of...     

Syntheses and studies of hydantoin derivatives as potential anti-tuberculosis inhibitors

A short and efficient synthesis of(Z)-2-substituted-5-(4-((2-substitued-5-oxoimidazolidin-4-ylidene)methyl)benzamido)ben-zoic acid derivatives(8a-g) as potential type of FabH inhibitors is described.Their structures were confirmed by MS,NOE and ~1H NMR.     

3D-QSAR,docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors

Janus kinase 3 (JAK3) is a promising drug target for the treatment of inflammatory diseases, autoimmune disorders, organ transplant rejection and various cancers. In the present study, 3D-QSAR, docking, MD simulation and MM/PBSA studies were performed on a series of pyrimidine-based JAK3 inhibitors. A reliable COMSIA (q² = 0.717 and r² = 0.986) model was developed and validated using external validation test set, bootstrapping, progressive scrambling and r_m² metrics analyses. Structural requirements identified through contour maps of the model were strategically utilized to computationally design 170 novel JAK3 inhibitors with improved potency. Docking studies were performed on the selected data set and newly designed compounds to show their binding mode and to identify important interacting residues inside the active site of JAK3. In addition, docking results of the selected designed compounds inside the active sites of JAK1, JAK2 and TYK2 indicated their JAK3 selectivity. MD simulation (100 ns) on the docked complex of compound 28 (one of highly active compounds of the data set) assisted in the further exploration of the binding interactions. Some crucial residues like Lys830 (glycine-rich loop), Val836, Ala853, Leu905 (hinge region), Cys909, Asn954, Leu956 and Ala966 were identified. Hydrogen bond interactions with hinge residue Leu905 were critical for the binding of JAK3 inhibitors. Additionally, MM/PBSA calculation provided the binding free energy of the compound 28. Newly designed molecules showed promising results in the preliminary in silico ADMET evaluations. Outcomes of the study can further be exploited to develop potent JAK3 inhibitors.     

Molecular docking studies on tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepinone (TIBO) derivatives as HIV-1 NNRT inhibitors

At present, chemotherapy seems to be the main weapon in the arsenal of remedies for the ongoing crusade against AIDS. The mode of binding of the TIBO family of inhibitors has been of interest because these compounds do not fit the two-hinged-ring model as generally observed in the NNRTIs. Flexible docking simulations were performed with a series of 53 TIBO derivatives as NNRTIs. Binding preferences as well as the structural and energetic factors associated with them were studied. A good correlation (r ² = 0.849, q ² = 0.843) was observed between the biological activity and binding affinity of the compounds which suggest that the identified binding conformations of these inhibitors are reliable. Further screening of PubChem database yielded novel scaffolds. Our studies suggest that modifications to the TIBO group of inhibitors might enhance their binding efficacy and hence, potentially, their therapeutic utility.     

Sub-structure-based screening and molecular docking studies of potential enteroviruses inhibitors

Rhinoviruses (RV), especially Human rhinovirus (HRVs) have been accepted as the most common cause for upper respiratory tract infections (URTIs). Pleconaril, a broad spectrum anti-rhinoviral compound, has been used as a drug of choice for URTIs for over a decade. Unfortunately, for various complications associated with this drug, it was rejected, and a replacement is highly desirable. In silico screening and prediction methods such as sub-structure search and molecular docking have been widely used to identify alternative compounds. In our study, we have utilised sub-structure search to narrow down our quest in finding relevant chemical compounds. Molecular docking studies were then used to study their binding interaction at the molecular level. Interestingly, we have identified 3 residues that is worth further investigation in upcoming molecular dynamics simulation systems of their contribution in stable interaction.     

Synthesis,evaluation and docking studies of some 4-thiazolone derivatives as effective lipoxygenase inhibitors

Some promising 4-thiazolone derivatives as lipoxygenase inhibitors were designed, synthesized, characterized and evaluated for anti-inflammatory activity and respective ulcerogenic liabilities. Compounds (1b, 1e, 3b, and 3e) exhibited considerable in vivo anti-inflammatory activity (57.61, 79.35, 75.00, and 79.35%) against carrageenan-induced rat paw edema model, whereas compounds (1e, 3b, and 3e) were found active against the arachidonic acid-induced paw edema model (55.38, 55.38, and 58.46%). The most potent compound (3e) exhibited lesser ulcerogenic liability compared to the standard diclofenac and zileuton. Further, the promising compounds (1e and 3e) were evaluated for in vitro lipoxygenase (LOX; IC₅₀?=?12.98 µM and IC₅₀?=?12.67 µM) and cyclooxygenase (COX) inhibition assay (COX-1; IC₅₀?>?50 µM and, COX-2; IC₅₀?>?50 µM). The enzyme kinetics of compound 3e was evaluated against LOX enzyme and supported by in silico molecular docking and molecular dynamics simulations studies. Overall, the results substantiated that 5-benzylidene-2-phenyl-4-thiazolones are promising pharmacophore for anti-inflammatory activity.     

Molecular docking,linear and nonlinear QSAR studies on factor Xa inhibitors

Structural Chemistry - Factor Xa (FXa) enzyme has an important role in the blood coagulation system. Disruption in the enzyme function results in the production of blood clots. Therefore,...     

Synthesis,biological evaluation and molecular docking study of pyrimidine based thiazolidinone derivatives as potential anti-urease and anti-cancer agents

Hybrid analogs containing molecules are always the choice of different synthetic researcher due to their diverse biological applications and significantly more efficient. Heterocyclic being a good inhibitors against varied disease are most commonly used in drug designing and development. The current study also addressed the synthesis of pyrimidine-based thiazolidinone derivatives (1–13) using stepwise processes and their structure was confirmed using various characterization techniques such as ¹HNMR, ¹³CNMR, and HREI-MS. Furthermore, the biological significances of the synthesized scaffolds were also explored and proved to be as anti-urease and anti-cancer moieties. Their inhibitory potentials were determined using the minimum inhibitory concentration (MIC) in the presence of their standard drugs, Thiourea (IC₅₀ = 8.20 ± 0.20 µM) and Tetrandrineb (IC₅₀ = 12.30 ± 0.10 µM) respectively. Structure activity relationship (SAR) was established for all the synthesized scaffolds and compared their inhibitory potentials in which scaffolds 3 (IC₅₀ = 2.30 ± 0.30 and 3.20 ± 0.50 µM), 6 (IC₅₀ = 3.10 ± 0.20 and 6.20 ± 0.10 µM), 7 (IC₅₀ = 3.20 ± 0.20 and 3.80 ± 0.30 µM) and 10 (IC₅₀ = 4.20 ± 0.20 and 5.10 ± 0.30 µM) exhibited the most influential activity. These compounds were subsequently examined using molecular docking experiments, which evaluate the binding interaction of ligands with enzyme active sites.     

Combined 2D and 3D-QSAR,molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors

Selective inhibition of phosphodiesterase 2 (PDE2) in cells where it is located elevates cyclic guanosine monophosphate (cGMP) and acts as novel analgesic with antinociceptive activity. Three-dimensional quantitative structure–activity relationship (QSAR) studies for pyrazolodiazepinone inhibitors exhibiting PDE2 inhibition were performed using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and Topomer CoMFA, and two-dimensional QSAR study was performed using a Hologram QSAR (HQSAR) method. QSAR models were generated using training set of 23 compounds and were validated using test set of nine compounds. The optimum partial least squares (PLS) for CoMFA-Focusing, CoMSIA-SDH, Topomer CoMFA and HQSAR models exhibited good ‘leave-one-out’ cross validated correlation coefficient (q²) of 0.790, 0.769, 0.840 and 0.787, coefficient of determination (r²) of 0.999, 0.964, 0.979 and 0.980, and high predictive power (r²_pred) of 0.796, 0.833, 0.820 and 0.803 respectively. Docking studies revealed that those inhibitors able to bind to amino acid Gln859 by cGMP binding orientation called ‘glutamine-switch’, and also bind to the hydrophobic clamp of PDE2 isoform, could possess high selectivity for PDE2. From the results of all the studies, structure–activity relationships and structural requirements for binding to active site of PDE2 were established which provide useful guidance for the design and future synthesis of potent PDE2 inhibitors.     

表皮生长因子受体和抑制剂之间分子对接的研究

研究了表皮生长因子受体(EGFR)和4-苯胺喹唑啉类抑制剂之间的相互作用模式，表皮生长因子受体的三维结构通过同源蛋白模建的方法得到，而抑制剂和靶酶结合复合物结构则通过分子力学和分子动力学结合的方法计算得到。从模拟结果得到的抑制剂和靶酶之间的相互作用模式表明范德华相互作用、疏水相互作用以及氢键相互作用对抑制剂的活性都有重要的影响，抑制剂的苯胺部分位于活性口袋的底部，能够与受体残基的非极性侧链产生很强的范德华和疏水相互作用，抑制剂双环上的取代基团也能和活性口袋外部的部分残基形成一定的范德华和疏水性相互作用，而抑制剂喹唑啉环上的氮原子能和周围的残基形成较强的氢键相互作用，对抑制剂的活性有较大的影响，计算得到抑制剂和靶酶之间的非键相互作用能以及抑制剂和靶酶之间的相互作用信息能够很好地解释抑制剂活性和结构的关系，为全新抑制剂的设计提供了重要的结构信息。     

Molecular modelling studies on cinnoline-based BTK inhibitors using docking and structure-based 3D-QSAR

ABSTRACT

BTK inhibitors have been proved as an effective target for B-cell malignancies. Ibrutinib is the most advanced irreversible BTK inhibitor for treating mantle cell lymphoma/chronic lymphocytic leukaemia but with existing drug resistance and adverse effects. To design novel effective and safety reversible BTK inhibitors, 115 newly cinnoline analogues were selected to perform molecular docking and 3D-QSAR study because of the main scaffold similarity to Ibrutinib. Both established CoMFA and CoMSIA models obtained high predictive and satisfactory value. CoMFA/CoMSIA contour maps demonstrated that bulky substitutions are preferred at R₁ and R₃ positions, and introducing hydrophilic and negative electrostatic substitutions at R₁ positions is important for improving BTK inhibitory activities. These results will be useful to provide clues for rationally designing novel and high potency BTK inhibitors.     

Extra precision docking,free energy calculation and molecular dynamics studies on glutamic acid derivatives as MurD inhibitors

The binding modes of well known MurD inhibitors have been studied using molecular docking and molecular dynamics (MD) simulations. The docking results of inhibitors 1-30 revealed similar mode of interaction with Escherichia coli-MurD. Further, residues Thr36, Arg37, His183, Lys319, Lys348, Thr321, Ser415 and Phe422 are found to be important for inhibitors and E. coli-MurD interactions. Our docking procedure precisely predicted crystallographic bound inhibitor 7 as evident from root mean square deviation (0.96 Å). In addition inhibitors 2 and 3 have been successfully cross-docked within the MurD active site, which was pre-organized for the inhibitor 7. Induced fit best docked poses of 2, 3, 7 and 15/2Y1O complexes were subjected to 10 ns MD simulations to determine the stability of the predicted binding conformations. Induce fit derived docked complexes were found to be in a state of near equilibrium as evident by the low root mean square deviations between the starting complex structure and the energy minimized final average MD complex structures. The results of molecular docking and MD simulations described in this study will be useful for the development of new MurD inhibitors with high potency.     

CoMFA and docking studies on glycogen phosphorylase a inhibitors as antidiabetic agents

Glycogen phosphorylase (GP(a)) is a specific target for the design of inhibitors and may prevent glycogenolysis under high glucose conditions in type II diabetes. The carboxamides first reported by Hoover D. J. et al. (J. Med. Chem. 1998, 41, 2934-2938) are one of the major classes of GP(a) inhibitors other than glucose derivatives. The recent, X-ray crystallographic analyses (Oikonomakos et al. Biochim. Biophys. Acta 2003, 1647, 325-332) have revealed a distinct mechanism of action for these inhibitors, which bind at a new allosteric site away from the inhibitory and catalytic sites. To elucidate the essential structural and physicochemical requirements responsible for binding to the GP(a) enzyme and to develop predictive models, CoMFA and docking studies have been carried out on a series of indole-2-carboxamide derivates. The CoMFA model developed using pharmacophoric alignments and hydrogen-bonding fields demonstrated high predictive ability against the training (r2 = 0.98, q2 = 0.68) and the test set (r2pred = 0.85). Further the superimposition of PLS coefficient contour maps from CoMFA with the GP(a) active site (PDB: 1lwo) has shown a high level of compatibility.     

Molecular docking studies of some new imidazole derivatives for antimicrobial properties

In modern drug designing, molecular docking is routinely used for understanding drug-receptor interaction. In the present study six imidazole derivatives containing substituted pyrazole moiety (2a,b and 4a–d) were synthesized. Structures of the newly synthesized compounds were characterized by spectral studies. Compounds were screened for their antibacterial activity. Compound 4c was found to be potent antimicrobial against Pseudomonas aeruginosa at concentrations of 1 and 0.5 mg/mL compared to standard drug Streptomycin. All the compounds were subjected to molecular docking studies for the inhibition of the enzyme l-glutamine: d-fructose-6-phosphate amidotransferase[GlcN-6-P] (EC 2.6.1.16). The in silico molecular docking study results showed that, all the synthesized compounds having minimum binding energy and have good affinity toward the active pocket, thus, they may be considered as good inhibitor of GlcN-6-P synthase.     

Eco-friendly synthesis of novel pyrimidine derivatives as potential anticancer agents

Herein, a rapid and highly efficient method for the synthesis of a new series of pyrimidine derivatives was demonstrated. The strategy was emanated from the reaction of hydrazinyl pyrimidine derivative ( 1 ) with different electrophilic species such as ethyl acetoacetate, ethyl 4,4,4-trifluoro acetoacetate, and phenyl isothiocyanate following cyclocondensation mechanism to afford the corresponding derivatives ( 2-6 ). Furthermore, condensation of hydrazine derivative ( 1 ) with different carbonyl compounds via conventional heating and microwave irradiation conditions was employed as a source of Schiff base derivatives bearing pyrimidine moiety ( 7-12 ). The structural features of all newly synthesized compounds were characterized by elemental and spectroscopic evidences. Some of the synthesized compounds were evaluated for in vitro cytotoxicity. The preliminary screening results showed that most of the tested compounds have moderate cytotoxic activity against HepG2 and HCT-116 cell lines. Finally, a molecular docking study was conducted to reveal the probable interaction with the thymidylate synthase enzyme.