Screening and docking studies of natural phenolic inhibitors of carbonic anhydrase II

Carbonic anhydrase II (CA II) is an important enzyme complex with Zn²⁺, which is involved in many physiological and pathological processes, such as calcification, glaucoma and tumorigenicity. In order to search for novel inhibitors of CA II, inhibition assay of carbonic anhydrase II was performed, by which seven natural phenolic compounds, including four phenolics (grifolin, 4-O-methyl-grifolic acid, grifolic acid, and isovanillic acid) and three flavones (eriodictyol, quercetin and puerin A), showed inhibitory activities against CA II with IC₅₀s in the range of 6.37–71.73 μmol/L. Grifolic acid is the most active one with IC₅₀ of 6.37 _μmol/L. These seven phenolic compounds were proved to be novel natural carbonic anhydrase II inhibitors, which were obtained in flexible docking study with GOLD 3.0 software. Results indicated that the aliphatic chain and polar groups of hydroxyl and carboxyl are important to their inhibitory activities, providing a new insight into study on CA II potent inhibitors. Authors with the equal contribution Supported by the National Natural Science Foundation of China (Grant No. 30725048) and the Foundation of Chinese Academy of Sciences (West Light Program).     

Theoretical improvement of the specific inhibitor of human carbonic anhydrase VII

The selectivity of a known arylsulfonamides inhibitor for two isozymes II and VII of human carbonic anhydrases (hCAs) was studied by homology modeling, molecular docking and molecular dynamics methods. The results show that the selectivity of the inhibitor for two isozymes is due to the different side chain lengths between N67 of hCA II and Q64 of hCA VII. One more methene group in the side chain of Q64 of hCA VII makes it possible to form the hydrogen bond with the bromide atom of the known inhibitor. From the point of view, the modification to the known inhibitor was performed to obtain an inhibitor with higher selectivity. The complex conformations of the new designed inhibitor and two isozymes designate the formation of the hydrogen bond between the newly added group (hydroxypropyl group) and Q64 of hCA VII but N67 of hCA II. The results of the binding free energy from the MM/PBSA approach also prove the selectivity improvement of the new inhibitor in comparison with the known inhibitor. The work will help the design of the isozyme-specific inhibitors of hCA VII.     

Evaluation of carbonic anhydrase and paraoxonase inhibition activities and molecular docking studies of highly water-soluble sulfonated phthalocyanines

The investigation of carbonic anhydrase and paraoxonase enzyme inhibition properties of water-soluble zinc and gallium phthalocyanine complexes ( 1 and 2 ) are reported for the first time. The binding of p-sulfonylphenoxy moieties to the phthalocyanine structure favors excellent solubilities in water, as well as providing an inhibition effect on carbonic anhydrase (CA) I and II isoenzymes and paraoxonase (PON1) enzyme. According to biological activity results, both complexes inhibited hCA I, hCA II, and PON1. Whereas 1 and 2 showed moderate hCA I and hCA II (off-target cytosolic isoforms) inhibitory activity (Ki values of 26.09 µM and 43.11 µM for hCA I and 30.95 µM and 33.19 µM for hCA II, respectively), they exhibited strong PON1 (associated with high-density lipoprotein [HDL]) inhibitory activity (Ki values of 0.37 µM and 0.27 µM, respectively). The inhibition kinetics were analyzed by Lineweaver–Burk double reciprocal plots. It revealed that 1 and 2 were noncompetitive inhibitors against PON1, hCA I, and hCA II. These complexes can be more advantageous than other synthetic CA and PON inhibitors due to their water solubility. Docking studies were carried out to examine the interactions between hCA I, hCA II, and PON1 inhibitors and metal complexes at a molecular level and to predict binding energies.     

Ligand‐based design,virtual screening,and ADME/T‐based profiling on a dataset of 1,3,5‐triazine‐substituted benzene sulfonamides as carbonic anhydrase inhibitors

A quantitative structure–activity relationship (QSAR) analysis was performed on a dataset of 62 (1,3,5‐triazine‐substituted) benzene sulfonamides as carbonic anhydrase II and IX inhibitors using simulated annealing‐based multiple linear regression analysis. The selected QSAR model for carbonic anhydrase II inhibition (cross‐validated Q² = 0.689, , ) showed that aromaticity, lipophilicity, electronegativity, and molecular projection in the XZ plane influence the activity, whereas that for carbonic anhydrase IX inhibition (cross‐validated Q² = 0.767, , ) showed that activity was influenced by hydrophilicity, linker between the aromatic rings, electronegativity, and molecular weight. The QSAR model selected was internally and externally validated to define its predictability. Activity prediction of an external dataset containing nine compounds (within the same sphere of applicability) was performed to prove the models' specificity, selectivity, and sensitivity. The hypothesis in the form of the QSAR model was used for ligand‐based virtual screening on the ZINC database to obtain some potential hits. Similarly, docking studies on screened hits showed that the molecules interact and orient at the catalytic site in a way similar to acetazolamide. Additionally, an absorption, distribution, metabolism, excretion, and toxicity screening was also performed, and results showed that most of the compounds that can be possible drug candidates obey the Lipinski rule of five and Jorgensen rule of three. Copyright © 2013 John Wiley & Sons, Ltd.     

Molecular description of pyrimidine-based inhibitors with activity against FAK combining 3D-QSAR analysis,molecular docking and molecular dynamics

Focal adhesion kinase (FAK) is a promising target for developing more effective anticancer drugs. To better understand the structure-activity relationships and mechanism of actions of FAK inhibitors, a molecular modeling study using 3D-QSAR, molecular docking, molecular dynamics simulations, and binding free energy analysis were conducted. Two types of satisfactory 3D-QSAR models were generated, comprising the CoMFA model (R²_cv = 0.528, R²_pred = 0.7557) and CoMSIA model (R²_cv = 0.757, R²_pred = 0.8362), for predicting the inhibitory activities of novel inhibitors. The derived contour maps indicate structural characteristics for substituents on the template. Molecular docking, molecular dynamic simulations and binding free energy calculations further reveal that the binding of inhibitors to FAK is mainly contributed from hydrophobic, electrostatic and hydrogen bonding interactions. In addition, some key residues (Arg14, Glu88, Cys90, Arg138, Asn139, Leu141, and Leu155) responsible for ligand-receptor binding are highlighted. All structural information obtained from 3D-QSAR models and molecular dynamics is consist with the available experimental activities. All the results will facilitate the optimization of this series of FAK inhibitors with higher inhibitory activities.     

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.     

Towards further understanding the structural insights of isoxazoles analogues against leishmaniasis using QSAR,molecular docking and molecular dynamics model

Leishmaniasis is one of the most well-known neglected infectious diseases, which is severe problem for public health. Heterocyclic derivatives are known to displays wide range of pharmacology activities including isoxazole ring that exhibit antileishmanial activity. Quantitative structure-activity relationship (QSAR) molecular docking and molecular dynamics are computational approaches to identify the relationships between structural properties and binding affinity of compounds. In the given paper series of 59, 4-aminomethyl 5-aryl-3-substituted isoxazoles were used to identify the structural insights and to find the binding affinity with protein. The designed model produced statistically significant results with of R² = 0.72, R²_adj = 0.65, and Q²_LMO = 0.72. Structure activity relationship (SAR) revealed that substitution of hydrophobic and steric groups may enhance the biological activity of compounds as antiprotozoal agents. Most potent compound formed hydrogen bonds with active amino acids Arg 87, Arg 104, Gly 112, His 117, Gly 118 and Asp 120. Molecular dynamics simulation (150 ns) on the docked complex of most active compound 3ba and 6 ab supported in the exploration of binding. Further MMPBSA investigations utilising MD trajectories verified compound 3bc higher binding affinity for nucleoside diphosphate kinases. The given strategies of computational studies could be an encouraging way for designing therapeutic targets against leishmaniasis.     

A structure-activity relationship study of catechol-O-methyltransferase inhibitors combining molecular docking and 3D QSAR methods

A panel of 92 catechol-O-methyltransferase (COMT) inhibitors was used to examine the molecular interactions affecting their biological activity. COMT inhibitors are used as therapeutic agents in the treatment of Parkinson's disease, but there are limitations in the currently marketed compounds due to adverse side effects. This study combined molecular docking methods with three-dimensional structure-activity relationships (3D QSAR) to analyse possible interactions between COMT and its inhibitors, and to incite the design of new inhibitors. Comparative molecular field analysis (CoMFA) and GRID/GOLPE models were made by using bioactive conformations from docking experiments, which yielded q2 values of 0.594 and 0.636, respectively. The docking results, the COMT X-ray structure, and the 3D QSAR models are in agreement with each other. The models suggest that an interaction between the inhibitor's catechol oxygens and the Mg2+ ion in the COMT active site is important. Both hydrogen bonding with Lys144, Asn170 and Glu199, and hydrophobic contacts with Trp38, Pro174 and Leu198 influence inhibitor binding. Docking suggests that a large R1 substituent of the catechol ring can form hydrophobic contacts with side chains of Val173, Leu198, Met201 and Val203 on the COMT surface. Our models propose that increasing steric volume of e.g. the diethylamine tail of entacapone is favourable for COMT inhibitory activity.     

Pharmacophore modeling,atom based 3D-QSAR,molecular docking and molecular dynamics studies on Escherichia coli ParE inhibitors

ATP dependent ParE enzyme is as an attractive target for the development of antibacterial agents. Atom based 3D-QSAR model AADHR.187 was developed based on the thirty eight Escherichia coli ParE inhibitors. The generated model showed statistically significant coefficient of determinations for the training (R² = 0.985) and test (R² = 0.86) sets. The cross-validated correlation coefficient (q2) was 0.976. The utility of the generated model was validated by the enrichment study. The model was also validated with structurally diverse external test set of ten compounds. Contour plot analysis of the generated model unveiled the chemical features necessary for the E. coli ParE enzyme inhibition. Extra-precision docking result revealed that hydrogen bonding and ionic interactions play a major role in ParE protein-ligand binding. Binding free energy was computed for the data set inhibitors to validate the binding affinity. A 30-ns molecular dynamics simulation showed high stability and effective binding of inhibitor 34 within the active site of ParE enzyme. Using the best fitted model AADHR.187, pharmacophore-based high-throughput virtual screening was performed to identify virtual hits. Based on the above studies three new molecules are proposed as E. coli ParE inhibitors with high binding affinity and favourable ADME properties.     

Identification of novel Plasmodium falciparum PI4KB inhibitors as potential anti-malarial drugs: Homology modeling,molecular docking and molecular dynamics simulations

The current study was set to discover selective Plasmodium falciparum phosphatidylinositol-4-OH kinase type III beta (pfPI4KB) inhibitors as potential antimalarial agents using combined structure-based and ligand-based drug discovery approach. A comparative model of pfPI4KB was first constructed and validated using molecular docking techniques. Performance of Autodock4.2 and Vina4 software in predicting the inhibitor-PI4KB binding mode and energy was assessed based on two Test Sets: Test Set I contained five ligands with resolved crystal structures with PI4KB, while Test Set II considered eleven compounds with known IC50 value towards PI4KB. The outperformance of Autodock as compared to Vina was reported, giving a correlation coefficient (R²) value of 0.87 and 0.90 for Test Set I and Test Set II, respectively. Pharmacophore-based screening was then conducted to identify drug-like molecules from ZINC database with physicochemical similarity to two potent pfPI4KB inhibitors –namely cpa and cpb. For each query inhibitor, the best 1000 hits in terms of TanimotoCombo scores were selected and subjected to molecular docking and molecular dynamics (MD) calculations. Binding energy was then estimated using molecular mechanics–generalized Born surface area (MM-GBSA) approach over 50 ns MD simulations of the inhibitor-pfPI4KB complexes. According to the calculated MM-GBSA binding energies, ZINC78988474 and ZINC20564116 were identified as potent pfPI4KB inhibitors with binding energies better than those of cpa and cpb, with ΔG_binding ≥ −34.56 kcal/mol. The inhibitor-pfPI4KB interaction and stability were examined over 50 ns MD simulation; as well the selectivity of the identified inhibitors towards pfPI4KB over PI4KB was reported.     

基于分子对接的thanatin与NDM-1分子动力学模拟研究

耐碳青霉烯类抗生素的超级细菌给人类健康带来了严重威胁,其所携带的金属 β-内酰胺酶编码基因是耐药性的主要来源。NDM-1作为其中传播最广、活性最强的 β-内酰胺酶,其抑制剂的研发刻不容缓。具有广谱作用的抗菌肽thanatin对NDM-1展现出了较好的抑制效果,但抑制机理并不清楚。本文使用HPEPDOCK与Rosetta FlexPepDock服务器,将thanatin与NDM-1进行了分子对接,并使用Desmond软件包对对接模型进行了分子动力学模拟。结果表明,thanatin与NDM-1活性中心的Zn2+ 并无直接相互作用,而作为竞争性抑制剂结合于NDM-1的活性口袋,阻止抗生素分子进入活性口袋与Zn2+ 结合,从而抑制NDM-1的水解活性。本文为研发有效的NDM临床抑制剂探索了可行的方法。     

The novel 4-hydroxyphenylpyruvate dioxygenase inhibitors in vivo and in silico approach: 3D-QSAR analysis,molecular docking,bioassay and molecular dynamics

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is not only an important target enzyme for the treatment of type I tyrosinemia, but also a new target for design bleaching herbicides, and it plays key role in the biosynthesis of tocopherol and plastoquinone. Thirty-six known active pyridine derivatives were collected, and comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models based on common skeleton were constructed to obtain novel HPPD herbicides with higher activity. Two new HPPD inhibitors were rationally designed and synthesized according to the CoMFA and CoMSIA models and verified by enzyme activity, biological assays, and molecular docking. The promising compound W1 ((E)-5-(3-(4-bromophenyl)acryloyl)-6-hydroxy-2,3-dihydropyridin-4(1H)-one) showed better AtHPPD inhibitory activity, and the bioassay results revealed that some weeds showed bleaching symptoms. The good binding stability of W1 and protein was confirmed by molecular dynamics simulation in 100 ns. These results would be highly useful in the progress of new HPPD inhibitors discovery.     

A selectivity study of benzenesulfonamide derivatives on human carbonic anhydrase II/IX by 3D-QSAR,Molecular Docking and Molecular Dynamics Simulation

Nowadays, different approaches have been pursued with the intent to develop sulfonamide-like carbonic anhydrase inhibitors that possess better selectivity profiles toward the different human isoforms of the enzyme. Here, we used conventional 3D-QSAR methods, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA, to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models for benzenesulfonamide derivatives as human carbonic anhydrase (hCA) II/IX inhibitors. The theoretical models had good reliability (R²>0.75) and predictability (Q²>0.55), and the contour maps could graphically present the contributions of the force fields for activity and identify the structural divergence between human carbonic anhydrase II inhibitors and human carbonic anhydrase IX inhibitors. Consequently, we explored the selectivity of inhibitor for human carbonic anhydrase II and IX through molecular docking, and the difference of activity coincides with the potential binding mode well. According to the results of the predicted values and the molecule docking, we found that the inhibitors published in the literature had stronger inhibition on the hCA IX; based on the theoretical models, we designed seven new compounds with good potential activity and reasonably good ADMET profile, which could selectively inhibit hCA IX. Molecular Dynamics Simulation showed that newly-designed compound D7 had good selectivity on hCA IX. The findings from 3D-QSAR and docking studies maybe helpful in the rational drug design of isoform-selective inhibitors.