Docking and molecular dynamics simulation of quinone compounds with trypanocidal activity

In this work, two different docking programs were used, AutoDock and FlexX, which use different types of scoring functions and searching methods. The docking poses of all quinone compounds studied stayed in the same region in the trypanothione reductase. This region is a hydrophobic pocket near to Phe396, Pro398 and Leu399 amino acid residues. The compounds studied displays a higher affinity in trypanothione reductase (TR) than glutathione reductase (GR), since only two out of 28 quinone compounds presented more favorable docking energy in the site of human enzyme. The interaction of quinone compounds with the TR enzyme is in agreement with other studies, which showed different binding sites from the ones formed by cysteines 52 and 58. To verify the results obtained by docking, we carried out a molecular dynamics simulation with the compounds that presented the highest and lowest docking energies. The results showed that the root mean square deviation (RMSD) between the initial and final pose were very small. In addition, the hydrogen bond pattern was conserved along the simulation. In the parasite enzyme, the amino acid residues Leu399, Met400 and Lys402 are replaced in the human enzyme by Met406, Tyr407 and Ala409, respectively. In view of the fact that Leu399 is an amino acid of the Z site, this difference could be explored to design selective inhibitors of TR. Docking and molecular dynamics simulation of genuine compounds with trypanocidal activity     

A theoretical investigation of cytotoxic activity of celastroid triterpenoids

Quantum chemical calculations at the B3LYP/6-31G* level of theory have been carried out on 20 celastroid triterpenoids to obtain a set of molecular electronic properties and to correlate these with cytotoxic activities. The cytotoxic activities of these compounds can be roughly correlated with electronic effects related to nucleophilic addition to C(6) of the compounds: The energies of the frontier molecular orbitals (E _HOMO and E _LUMO), the HOMO-LUMO energy gap, the dipole moment, the charge on C(6), and the electrophilicity on C(6). Figure LUMO of Pristimerin.     

Molecular docking,molecular modeling,and molecular dynamics studies of azaisoflavone as dual COX-2 inhibitors and TP receptor antagonists

Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4-one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes.

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Study of a ligand complexed with Cdk2/Cdk4 by computer simulation

Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745–749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2 (K _i =6 nM) but a low affinity with cyclin-dependent kinase 4 (K _i =1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy calculations to analyze the interactions. A rational 3D model of the Cdk4–NU6102 complex is built. Asp86 is a key residue that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4. Figure Two-dimensional representative for the interacting model of NU6102 complexed with the Cdk4 from a predicted structure by LIGPLOT.      

Homology modeling of a novel epoxide hydrolase (EH) from Aspergillus niger SQ-6: structure-activity relationship in expoxides inhibiting EH activity

The 3D structure of a novel epoxide hydrolase from Aspergillus niger SQ-6 (sqEH) was constructed by using homology modeling and molecular dynamics simulations. Based on the 3D model, Asp191, His369 and Glu343 were predicted as catalytic triad. The putative active pocket is a hydrophobic environment and is rich in some important non—polar residues (Pro318, Trp282, Pro319, Pro317 and Phe242). Using three sets of epoxide inhibitors for docking study, the interaction energies of sqEH with each inhibitor are consistent with their inhibitory effects in previous experiments. Moreover, a critical water molecule which closes to the His369 was identified to be an ideal position for the hydrolysis step of the reaction. Two tyrosine residues (Tyr249 and Tyr312) are able to form hydrogen bonds with the epoxide oxygen atom to maintain the initial binding and positioning of the substrate in the active pocket. These docked complex models can well interpret the substrate specificity of sqEH, which could be relevant for the structural—based design of specific epoxide inhibitors. Figure       

Exploring the binding pocket for pyridopyrimidine ligands at the CCK1 receptor by molecular docking

Pyridopyrimidine-based analogues are among the most highly potent and selective antagonists of cholecystokinin receptor subtype-1 (CCK1R) described to date. To better understand the structural and chemical features responsible for the recognition mechanism, and to explore the binding pocket of these compounds, we performed automated molecular docking using GOLD2.2 software on some derivatives with structural diversity, and propose a putative binding conformation for each compound. The docking protocol was guided by the key role of the Asn333 residue, as revealed by site directed mutagenesis studies. The results suggest two putative binding modes located in the same pocket. Both are characterized by interaction with the main residues revealed by experiment, Asn333 and Arg336, and differ in the spatial position of the Boc-Trp moiety of these compounds. Hydrophobic contacts with residues Thr117, Phe107, Ile352 and Ile329 are also in agreement with experimental data. Despite the poor correlation obtained between the estimated binding energies and the experimental activity, the proposed models allow us to suggest a plausible explanation of the observed binding data in accordance with chemical characteristics of the compounds, and also to explain the observed diastereoselectivity of this family of antagonists towards CCK1R. The most reasonable selected binding conformations could be the starting point for future studies. Figure Superimposition of the two putative binding conformations revealed by molecular docking for pyridopyrimidine-based CCK1 antagonists     

Docking studies suggest ligand-specific δ-opioid receptor conformations

An automated docking procedure was used to study binding of a series of δ-selective ligands to three models of the δ-opioid receptor. These models are thought to represent the three ligand-specific receptor conformations. Docking results are in agreement with point mutation studies and suggest that different ligands—agonists and antagonists—may bind to the same binding site under different receptor conformations. Docking to different receptor models (conformations) also suggests that by changing to a receptor-specific conformation, the receptor may open or close different binding sites to other ligands. Figure  Ligands 5 (green) and 6 (orange) in bindingpocket BP1 of the R1 δ-opioid receptor model     

Quinoline alkaloids as intercalative topoisomerase inhibitors

Quinoline alkaloids are abundant in the Rutaceae, and many have exhibited cytotoxic activity. Because structurally related antitumor alkaloids such as camptothecin and fagaronine are known to function as intercalative topoisomerase poisons, it is hypothesized that cytotoxic Stauranthus alkaloids may also serve as intercalative topoisomerase inhibitors. To test this hypothesis theoretically, ten Stauranthus quinoline alkaloids were examined for potential intercalation into DNA using a molecular docking approach. Four of the alkaloids (stauranthine, skimmianine, 3′,6′-dihydroxy-3′,6′-dihydrostauranthine, and trans-3′,4′-dihydroxy-3′,4′-dihydrostauranthine) were able to intercalatively dock consistently into DNA. In order to probe the intermolecular interactions that may be responsible for intercalation of these quinoline alkaloids, density functional calculations have been carried out using both the B3LYP and M06 functionals. M06 calculations indicated favorable π–π interactions between either skimmianine or stauranthine and the guanine–cytosine base pair. Furthermore, the lowest-energy face-to-face orientation of stauranthine with guanine is consistent with favorable dipole–dipole orientations, favorable electrostatic interactions, and favorable frontier molecular orbital interactions. Likewise, the lowest-energy face-to-face orientation of stauranthine with the guanine–cytosine base pair reveals favorable electrostatic interactions as well as frontier molecular orbital interactions. Thus, not only can quinoline alkaloids dock intercalatively into DNA, but the docked orientations are also electronically favorable.      

Docking studies on kinesin spindle protein inhibitors: an important cooperative ‘minor binding pocket’ which increases the binding affinity significantly

Fifteen KSP inhibitors were docked into the receptor and the binding mode was analyzed for the first time. It was considered that in addition to the main binding pocket all the inhibitors merged in, there exists a cooperative minor binding pocket, which could be explored for significantly increased binding affinity. In addition, a good linear relationship between the biological activities and the lowest binding free energies has also been found. This may help in predicting the binding affinity of newly designed KSP inhibitors. Figure Two binding pockets considered after the analysis. Seven docked ligands (compound 1–7) were overlapped at the binding site. All inhibitors tested interacted with the main pocket, while CK0106023, interacted also with the cooperative minor pocket mainly surrounded by Arg221 and Ala218. Coloring of the binding site surface are different ends of each amino acid residue: blue represents amino group while red means carboxyl     

Computer-based design of novel HIV-1 entry inhibitors: neomycin conjugated to arginine peptides at two specific sites

Aminoglycoside–arginine conjugates (AAC and APAC) are multi-target inhibitors of human immunodeficiency virus type-1 (HIV-1). Here, we predict new conjugates of neomycin with two arginine peptide chains binding at specific sites on neomycin [poly-arginine-neomycin-poly-arginine (PA-Neo-PA)]. The rationale for the design of such compounds is to separate two short arginine peptides with neomycin, which may extend the binding region of the CXC chemokine receptor type 4 (CXCR4). We used homology models of CXCR4 and unliganded envelope glycoprotein 120 (HIV-1_IIIB gp120) and docked PA-Neo-PAs and APACs to these using a multistep docking procedure. The results indicate that PA-Neo-PAs spread over two negatively charged patches of CXCR4. PA-Neo-PA–CXCR4 complexes are energetically more favorable than AACs/APAC–CXCR4 complexes. Notably, our CXCR4 model and docking procedure can be applied to predict new compounds that are either inhibitors of gp120–CXCR4 binding without affecting stromal cell-derived factor 1α (SDF-1α) chemotaxis activity, or inhibitors of SDF-1α–CXCR4 binding resulting in an anti-metastasis effect. We also predict that PA-Neo-PAs and APACs can interfere with CD4–gp120 binding in unliganded conformation. Figure The r5-Neo-r5-CXCR4 complex. CXCR4 is shown in CPK representation. The negatively charged residues are shown in red and positively charged residues in blue. The r5-Neo-r5 is shown in stick representation, neomycin core is colored yellow and arginine moieties are colored magenta. Two negatively charged patches separated by neutral and positively charged residues are visible.     

Toward the virtual screening of Cdc25A phosphatase inhibitors with the homology modeled protein structure

Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapy due to the correlation of their overexpression with a wide variety of cancers. As a method for the discovery of novel inhibitors of Cdc25 phosphatases, we have evaluated the computer-aided drug design protocol involving the homology modeling of Cdc25A and virtual screening with the two docking tools: FlexX and the modified AutoDock program implementing the effects of ligand solvation in the scoring function. The homology modeling with the X-ray crystal structure of Cdc25B as a template provides a high-quality structure of Cdc25A that enables the structure-based inhibitor design. Of the two docking programs under consideration, AutoDock is found to be more accurate than FlexX in terms of scoring putative ligands. A detailed binding mode analysis of the known inhibitors shows that they can be stabilized in the active site of Cdc25A through the simultaneous establishment of the multiple hydrogen bonds and the hydrophobic interactions. The present study demonstrates the usefulness of the modified AutoDock program as a docking tool for virtual screening of new Cdc25 phosphatase inhibitors as well as for binding mode analysis to elucidate the activities of known inhibitors. Figure Structures and available IC50 values (in μM) of the twenty Cdc25 phosphatase inhibitors seeded in docking library     

Mechanistic study of palladium-catalyzed telomerization of 1,3-butadiene with methanol

The Pd-catalyzed telomerization in the presence of phosphine and carbene ligands has been computed. It is shown that the C–C coupling of the less stable complex A with one trans- and one cis-butadiene in syn orientation forms the most stable intermediate B and is favorable both kinetically and thermodynamically. Protonation of B leads to equilibrium of the two most stable isomers of intermediate C. The overall regioselectivity is favored thermodynamically.      

Comparing the electronic properties and docking calculations of heme derivatives on CYP2B4

Cytochrome P-450 is a group of enzymes involved in the biotransformation of many substances, including drugs. These enzymes possess a heme group (1) that when it is properly modified induces several important physicochemical changes that affect their enzymatic activity. In this work, the five structurally modified heme derivatives 2–6 and the native heme 1 were docked on CYP2B4, (an isoform of P450), in order to determine whether such modifications alter their binding form and binding affinity for CYP2B4 apoprotein. In addition, docking calculations were used to evaluate the affinity of CYP2B4 apoprotein-heme complexes for aniline (A) and N-methyl-aniline (NMA). Results showing the CYP2B4 heme 4- and heme 6-apoprotein complexes to be most energetically stable indicate that either hindrance effects or electronic properties are the most important factors with respect to the binding of heme derivatives at the heme-binding site. Furthermore, although all heme-apoprotein complexes demonstrated high affinity for both A and NMA, the CYP2B4 apoprotein-5 complex had higher affinity for A, and the heme 6 complex had higher affinity for NMA. Finally, surface electronic properties (SEP) were calculated in order to explain why certain arginine residues of CYP2B4 apoprotein interact with polarizable functionalities, such as ester groups or sp ² carbons, present in some heme derivates. The main physicochemical parameter involved in the recognition process of the heme derivatives, the CYP2B4 apoprotein and A or NMA, are reported. Figure Scheme of steps to be followed for obtaining five new CYP2B4 apoprotein-heme complexes by docking     

Molecular models of protein kinase 6 from Plasmodium falciparum

Cyclin-dependent kinases (CDKs) have been identified as potential targets for development of drugs, mainly against cancer. These studies generated a vast library of chemical inhibitors of CDKs, and some of these molecules can also inhibit kinases identified in the Plasmodium falciparum genome. Here we describe structural models for Protein Kinase 6 from P. falciparum (PfPK6) complexed with Roscovitine and Olomoucine. These models show clear structural evidence for differences observed in the inhibition, and may help designing inhibitors for PfPK6 generating new potential drugs against malaria. Figure Ribbon diagram of PfPK6 complexed with a roscovitine and b olomoucine     

3D-QSAR studies of Dipeptidyl peptidase IV inhibitors using a docking based alignment

Dipeptidyl peptidase IV (DPP-IV) deactivates the incretin hormones GLP-1 and GIP by cleaving the penultimate proline or alanine from the N-terminal (P1-position) of the peptide. Inhibition of this enzyme will prevent the degradation of the incretin hormones and maintain glucose homeostasis; this makes it an attractive target for the development of drugs for diabetes. This paper reports 3D-QSAR analysis of several DPP-IV inhibitors, which were aligned by the receptor-based technique. The conformation of the molecules in the active site was obtained through docking methods. The QSAR models were generated on two training sets composed of 74 and 25 molecules which included phenylalanine, thiazolidine, and fluorinated pyrrolidine analogs. The 3D-QSAR models are robust with statistically significant r², q², and values. The CoMFA and CoMSIA models were used to design some new inhibitors with several fold higher binding affinity. Figure The CoMFA contours around molecule D1T155 (a) steric contours - favored (green); disfavored (yellow) (b) electrostatic contours - electropositive (blue); electronegative (red)     

Theoretical study on the thermal decomposition of model compounds for Poly (dialkyl fumarate)

The thermal decomposition of model compounds for poly (dialkyl fumarate) was studied by using ab initio and density functional theory (DFT) calculations. To determine the most favorable reaction pathway of thermal decomposition, geometries, structures, and energies were evaluated for reactants, products, and transition states of the proposed pathways at the HF/6-31G(d) and B3LYP/6-31G(d) levels. Three possible paths (I, II and III) and subsequent reaction paths (IV and V) for the model compounds of poly (dialkyl fumarate) decomposition had been postulated. It has been found that the path (I) has the lowest activation energy 193.8 kJ mol⁻¹ at B3LYP/6-31G(d) level and the path (I) is considered as the main path for the thermal decomposition of model compounds for poly (dialkyl fumarate).