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PubMed2003

Detailed analysis of grid-based molecular docking: A case study of CDOCKER-A CHARMm-based MD docking algorithm.

The influence of various factors on the accuracy of protein-ligand docking is examined. The factors investigated include the role of a grid representation of protein-ligand interactions, the initial ligand conformation and orientation, the sampling rate of the energy hyper-surface, and the final minimization. A representative docking method is used to study these factors, namely, CDOCKER, a molecular dynamics (MD) simulated-annealing-based algorithm. A major emphasis in these studies is to compare the relative performance and accuracy of various grid-based approximations to explicit all-atom force field calculations. In these docking studies, the protein is kept rigid while the ligands are treated as fully flexible and a final minimization step is used to refine the docked poses. A docking success rate of 74% is observed when an explicit all-atom representation of the protein (full force field) is used, while a lower accuracy of 66-76% is observed for grid-based methods. All docking experiments considered a 41-member protein-ligand validation set. A significant improvement in accuracy (76 vs. 66%) for the grid-based docking is achieved if the explicit all-atom force field is used in a final minimization step to refine the docking poses. Statistical analysis shows that even lower-accuracy grid-based energy representations can be effectively used when followed with full force field minimization. The results of these grid-based protocols are statistically indistinguishable from the detailed atomic dockings and provide up to a sixfold reduction in computation time. For the test case examined here, improving the docking accuracy did not necessarily enhance the ability to estimate binding affinities using the docked structures.

Algorithms↗
PubMed2006

The productive conformation of prostaglandin G2 at the peroxidase site of prostaglandin endoperoxide H synthase: docking, molecular dynamics, and site-directed mutagenesis studies.

We present a plausible productive conformation obtained by docking calculations for the binding of prostaglandin G2 (PGG2) to the peroxidase site of prostaglandin endoperoxide H synthase-1 (PGHS-1, COX-1). The enzyme-substrate complex stability was verified by molecular dynamics. Structural analysis reveals the requirements for enzyme-substrate recognition and binding: the PGG2 15-hydroperoxide group is in the proximity of the heme iron and participates in a hydrogen bond network with the conserved His207 and Gln203 and a water molecule, whereas the carboxylate group forms salt bridges with the remote Lys215 and Lys222. Site-directed mutagenesis showed that a single mutation of Lys215 or Lys222 does not affect enzyme activity, whereas dual mutation of these residues, to either alanine or glutamate, significantly decreases turnover. This indicates that the conserved cationic pocket is involved in enzyme-substrate binding.

Amino Acid Sequence↗
PubMed2005

Molecular docking and 3D-QSAR studies of Yersinia protein tyrosine phosphatase YopH inhibitors.

Three-dimensional quantitative structure-activity relationship (QSAR) studies were conducted on two classes of recently explored compounds with known YopH inhibitory activities. Docking studies were employed to position the inhibitors into the YopH active site to determine the probable binding conformation. Good correlations between the predicated binding free energies and the inhibitory activities were found for two subsets of phosphate mimetics: alpha-ketocarboxylic acid and squaric acid (R2=0.70 and 0.68, respectively). The docking results also provided a reliable conformational alignment scheme for 3D-QSAR modeling. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed based on the docking conformations, giving q2 of 0.734 and 0.754 for CoMFA and CoMSIA models, respectively. The 3D-QSAR models were significantly improved after removal of an outlier (q2=0.829 for CoMFA and q2=0.837 for CoMSIA). The predictive ability of the models was validated using a set of compounds that were not included in the training set. Mapping the 3D-QSAR models to the active site of YopH provides new insight into the protein-inhibitor interactions for this enzyme. These results should be applicable to the prediction of the activities of new YopH inhibitors, as well as providing structural implications for designing potent and selective YopH inhibitors as antiplague agents.

Bacterial Outer Membrane Proteins↗
PubMed2004

Molecular docking and 3D QSAR studies on 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes based on the structural modeling of human CCR5 receptor.

In the present study, we have used an approach combining protein structure modeling, molecular dynamics (MD) simulation, automated docking, and 3D QSAR analyses to investigate the detailed interactions of CCR5 with their antagonists. Homology modeling and MD simulation were used to build the 3D model of CCR5 receptor based on the high-resolution X-ray structure of bovine rhodopsin. A series of 64 CCR5 antagonists, 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes, were docked into the putative binding site of the 3D model of CCR5 using the docking method, and the probable interaction model between CCR5 and the antagonists were obtained. The predicted binding affinities of the antagonists to CCR5 correlate well with the antagonist activities, and the interaction model could be used to explain many mutagenesis results. All these indicate that the 3D model of antagonist-CCR5 interaction is reliable. Based on the binding conformations and their alignment inside the binding pocket of CCR5, three-dimensional structure-activity relationship (3D QSAR) analyses were performed on these antagonists using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods. Both CoMFA and CoMSIA provide statistically valid models with good correlation and predictive power. The q(2)(r(cross)(2)) values are 0.568 and 0.587 for CoMFA and CoMSIA, respectively. The predictive ability of these models was validated by six compounds that were not included in the training set. Mapping these models back to the topology of the active site of CCR5 leads to a better understanding of antagonist-CCR5 interaction. These results suggest that the 3D model of CCR5 can be used in structure-based drug design and the 3D QSAR models provide clear guidelines and accurate activity predictions for novel antagonist design.

Binding Sites↗
PubMed2000

QSD quadratic shape descriptors. 2. Molecular docking using quadratic shape descriptors (QSDock).

We present a new shape-based polynomial time algorithm for the rapid docking of rigid ligands into their macromolecular receptors. The method exploits molecular surface complementarity existing between a putative ligand and its receptor protein. Molecular shapes are represented by using a new shape descriptor that is based on local quadratic approximations to the molecular surface. The quadratic shape descriptor is capable of representing a plethora of molecular shapes and is not limited to describing convex or concave regions of molecular surface. A single pair of complementary descriptors is sufficient for computing the transformation matrix that positions a ligand into the receptor site. We demonstrate the capabilities of our algorithm by successfully reproducing the crystallographically determined orientation for a test set of 20 ligand-protein complexes.

Algorithms↗
PubMed2005

Characterization of binding site of closed-state KCNQ1 potassium channel by homology modeling, molecular docking, and pharmacophore identification.

This investigation was performed to assess the importance of interaction in the binding of blockers to KCNQ1 potassium using molecular modeling. This work could be considered made up by three main steps: (1) the construction of closed-state structure of KCNQ1 through homology modeling; (2) the automated docking of three blockers: IKS-142, L-735821, and BMS-IKS, using DOCK program; (3) the generation and validation of pharmacophore for KCNQ1 ligands using Catalyst/HypoGen. The obtained results highlight the hydrophobic or aromatic residues involved in S6 transmembrane domain and the base of the pore helix of KCNQ1, confirming the mutagenesis data and pharmacophore model, and giving new suggestions for the rational design of novel KCNQ1 ligands.

Amino Acid Sequence↗
PubMedDate not supplied

Mapping the binding site of a large set of quinazoline type EGF-R inhibitors using molecular field analyses and molecular docking studies.

In the current work, three-dimensional QSAR studies for one large set of quinazoline type epidermal growth factor receptor (EGF-R) inhibitors were conducted using two types of molecular field analysis techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). These compounds belonging to six different structural classes were randomly divided into a training set of 122 compounds and a test set of 13 compounds. The statistical results showed that the 3D-QSAR models derived from CoMFA were superior to those generated from CoMSIA. The most optimal CoMFA model after region focusing bears significant cross-validated r(2)(cv) of 0.60 and conventional r(2) of 0.92. The predictive power of the best CoMFA model was further validated by the accurate estimation to these compounds in the external test set, and the mean agreement of experimental and predicted log(IC(50)) values of the inhibitors is 0.6 log unit. Separate CoMFA models were conducted to evaluate the influence of different partial charges (Gasteiger-Marsili, Gasteiger-Hückel, MMFF94, ESP-AM1, and MPA-AM1) on the statistical quality of the models. The resulting CoMFA field map provides information on the geometry of the binding site cavity and the relative weights of various properties in different site pockets for each of the substrates considered. Moreover, in the current work, we applied MD simulations combined with MM/PBSA (Molecular mechanics/Possion-Boltzmann Surface Area) to determine the correct binding mode of the best inhibitor for which no ligand-protein crystal structure was present. To proceed, we define the following procedure: three hundred picosecond molecular dynamics simulations were first performed for the four binding modes suggested by DOCK 4.0 and manual docking, and then MM/PBSA was carried out for the collected snapshots. The most favorable binding mode identified by MM/PBSA has a binding free energy about 10 kcal/mol more favorable than the second best one. The most favorable binding mode identified by MM/PBSA can give satisfactory explanation of the SAR data of the studied molecules and is in good agreement with the contour maps of CoMFA. The most favorable binding mode suggests that with the quinazoline-based inhibitor, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 766, not Thr 830 as proposed by Wissner et al. (J. Med. Chem. 2000, 43, 3244). The predicted complex structure of quinazoline type inhibitor with EGF-R as well as the pharmacophore mapping from CoMFA can interpret the structure activities of the inhibitors well and afford us important information for structure-based drug design.

Binding Sites↗
PubMed2003

Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (irinotecan, CPT-11) is a camptothecin prodrug that is metabolized by carboxylesterases (CE) to the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), a topoisomerase I inhibitor. CPT-11 has shown encouraging antitumor activity against a broad spectrum of tumor types in early clinical trials, but hematopoietic and gastrointestinal toxicity limit its administration. To increase the therapeutic index of CPT-11 and to develop other prodrug analogues for enzyme/prodrug gene therapy applications, our laboratories propose to develop camptothecin prodrugs that will be activated by specific CEs. Specific analogues might then be predicted to be activated, for example, predominantly by human liver CE(hCE1), by human intestinal CE (hiCE), or in gene therapy approaches using a rabbit liver CE (rCE). This study describes a molecular modeling approach to relate the structure of rCE-activated camptothecin prodrugs with their biological activation. Comparative molecular field analysis, comparative molecular similarity index analysis, and docking studies were used to predict the biological activity of a 4-benzylpiperazine derivative of CPT-11 [7-ethyl-10-[4-(1-benzyl)-1-piperazino]carbonyloxycamptothecin (BP-CPT)] in U373MG glioma cell lines transfected with plasmids encoding rCE or hiCE. BP-CPT has been reported to be activated more efficiently than CPT-11 by a rat serum esterase activity; however, three-dimensional quantitative structure-activity relationship studies predicted that rCE would activate BP-CPT less efficiently than CPT-11. This was confirmed by both growth inhibition experiments and kinetic studies. The method is being used to design camptothecin prodrugs predicted to be activated by specific CEs.

Animals↗
PubMed2005

Cell adhesion inhibitory activity of (d)-corynoline, a hexahydrobenzo[c]phenanthridine-type alkaloid, and its structure-activity relationship, studied by X-ray crystal structure analysis and molecular docking study.

Corynoline (1), a hexahydrobenzo[c]phenanthridine-type alkaloid, exhibited the concentration-dependent inhibition for the adhesion of human polymorphonuclear leukocyte and eosinophil to human umbilical vein cultured endothelial cell in the concentration range of showing no significant cytotoxicity for the cell: IC(50) value=72.4 microM for (d)-1 and 156.7 microM for (l)-1. This shows the potent anti-inflammatory and/or immunosuppressive activity of 1. To elucidate possible structure-activity relationship, the conformational/structural feature of (d)-1 was investigated by X-ray crystal structure analysis and molecular orbital energy calculations, and the docking study was performed for its interaction with the D1-domain of ICAM-1 (intracellular adhesion molecule-1). A plausible model was proposed, in which all polar atoms of (d)-1 are linked by hydrogen bonds or electrostatic interactions with the functional residues of ICAM-1, that have been supposed to be necessary for the binding with LFA-1 (leukocyte function-associated antigen-1). This suggests the potent inhibitory activity of 1 for the ICAM-1/LFA-1 adhesion and would be important on developing the clinically usable drugs for the inflammatory diseases.

Berberine Alkaloids↗
PubMedDate not supplied

Modeling ligand-receptor interaction for some MHC class II HLA-DR4 peptide mimetic inhibitors using several molecular docking and 3D QSAR techniques.

The ligand-receptor interaction between some peptidomimetic inhibitors and a class II MHC peptide presenting molecule, the HLA-DR4 receptor, was modeled using some three-dimensional (3D) quantitative structure-activity relationship (QSAR) methods such as the Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Indices Analysis (CoMSIA), and a pharmacophore building method, the Catalyst program. The structures of these peptidomimetic inhibitors were generated theoretically, and the conformations used in the 3D QSAR studies were defined by docking them into the known structure of HLA-DR4 receptor through the GOLD, GLIDE Rigidly, GLIDE Flexible, and Xscore programs. Some of the parameters used in these docking programs were selected by docking an X-ray ligand into the receptor and comparing the root-means-square difference (RMSD) computed between the coordinates of the X-ray and docked structure. However, the goodness of a docking result for docking a series of peptidomimetic inhibitors into the HLA-DR4 receptor was judged by comparing the Spearman's rank correlation coefficient computed between each docking result and the activity data taken from the literature. The best CoMFA and CoMSIA models were constructed using the aligned structures of the best docking result. The CoMSIA was conducted in a stepwise manner to identify some important molecular features that were further employed in a pharmacophore building process by the Catalyst program. It was found that most inhibitors of the training set were accurately predicted by the best pharmacophore model, the Hypo1 hypothesis constructed. The deviation or conflict found between the actual and predicted activities of some inhibitors of both the training and the test sets were also investigated by mapping the Hypo1 hypothesis onto the corresponding structures of the inhibitors.

Binding Sites↗
PubMed2026

Matrine Alleviates Sepsis-Induced Acute Lung Injury by Reinforcing NQO1/SLC7A11/GPX4-Associated Anti-Ferroptotic Defenses and Attenuating NF-κB-Driven Inflammation.

BACKGROUND: Sepsis triggers dysregulated systemic inflammation and multiple-organ dysfunction, with the lungs being particularly susceptible to injury. Sepsis-induced acute respiratory distress syndrome (ARDS) is mainly driven by TLR4/NF-κB-mediated hyperinflammation and alveolar macrophage activation. Matrine, a bioactive alkaloid derived from Sophora flavescens, has been reported to modulate redox homeostasis and ferroptosis-associated lipid peroxidation. However, the target-specific mechanisms underlying its effects on ferroptosis and inflammatory signaling in sepsis-induced acute lung injury (SALI) remain incompletely understood. PURPOSE: This study aimed to evaluate the therapeutic effects of matrine in a cecal ligation and puncture (CLP)-induced SALI model and to determine whether its protective effects involve reinforcement of NQO1/SLC7A11/GPX4-associated anti-ferroptotic defenses and suppression of NF-κB-driven inflammation. METHODS: We analyzed the single-cell RNA-sequencing (scRNA-seq) dataset GSE273924 to characterize CD45-enriched pulmonary immune-cell subsets in sham mice and mice with intratracheal Escherichia coli-induced pneumonia. Network pharmacology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict Kushen (KS)-related targets and pathways associated with SALI. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) of GSE245013 were used to identify candidate targets. Matrine-NQO1 binding and intracellular target engagement were evaluated using molecular docking, molecular dynamics simulations, surface plasmon resonance (SPR), and the cellular thermal shift assay (CETSA). The therapeutic effects of matrine were assessed in mice with CLP-induced SALI and in lipopolysaccharide (LPS)-stimulated MH-S cells. Lung histopathology, inflammatory cytokine production, target protein expression, ferroptosis-associated indicators, and NF-κB activation were evaluated using molecular, biochemical, and histological assays. The functional contribution of NQO1 was further examined using the NQO1 inhibitor ES936. RESULTS: scRNA-seq analysis of GSE273924 revealed substantial remodeling of the CD45-enriched pulmonary immune-cell landscape in mice with intratracheal E. coli-induced pneumonia, including macrophage transcriptional programs associated with ferroptosis and inflammatory signaling. Integrated network pharmacology and bioinformatics analyses prioritized NQO1 as a candidate target of matrine and identified NF-κB signaling as a potentially relevant pathway. Molecular docking, molecular dynamics simulations, SPR, and CETSA supported matrine-NQO1 binding and intracellular target engagement. Functionally, matrine improved survival, attenuated lung injury, reinforced NQO1/SLC7A11/GPX4-associated anti-ferroptotic defenses, and suppressed NF-κB activation in CLP mice. Similar protective effects were observed in LPS-stimulated MH-S cells. ES936 partially attenuated the matrine-mediated improvements in cell viability, redox homeostasis, ferroptosis-associated indicators, and NF-κB p65 phosphorylation, supporting a functional contribution of NQO1 to the protective effects of matrine. CONCLUSION: Matrine alleviates SALI by reinforcing NQO1/SLC7A11/GPX4-associated anti-ferroptotic defenses and attenuating NF-κB-driven inflammation.

Animals↗
PubMed2003

Molecular docking of substrates and inhibitors in the catalytic site of CYP6B1, an insect cytochrome p450 monooxygenase.

Furanocoumarins represent plant toxins that are used in the treatment of a variety of skin diseases and are metabolized by cytochrome p450 monooxygenases (p450s) existing in insects such as Papilio polyxenes (the black swallowtail). To elucidate the active site in the CYP6B1 protein that is the principal p450 existing in this species, we have constructed a homology model of it based on sequence and structure alignments with the bacterial CYP102 protein whose crystal structure has been defined and with the insect CYP6B4 protein that also metabolizes furanocoumarins. In the derived CYP6B1 model, Phe116 and His117 in SRS1, Phe371 in SRS5 and Phe484 in SRS6 contribute to the formation of a resonant network that stabilizes the p450's catalytic site and allows for interactions with its furanocoumarin substrates. The first two of these residues are absolutely conserved in all members of the insect CYP6B subfamily and the last two are variable in different members of the CYP6B subfamily. A combination of theoretical and experimental docking analyses of two substrates (xanthotoxin and bergapten) and two inhibitors (coumarin and pilocarpine) of this p450 provide significant information on the positioning of furanocoumarins within this catalytic pocket. Molecular replacement models based on the results of variations at two of these critical amino acids provide support for our furanocoumarin-docked model and begin to rationalize the altered substrate reactivities observed in experimental analyses.

5-Methoxypsoralen↗
PubMed2003

3-D-QSAR study and molecular docking of methionyl-tRNA synthetase inhibitors.

The three-dimensional quantitative structure-activity relationships of 57 2-[(aminopropyl)amino]-4(1H)-quinolinone analogues as Staphylococcus aureus methionyl-tRNA synthetase (MetRS) inhibitors with excellent antibacterial profile were investigated and docking studies were performed. The CoMFA analysis provided a model with a q(2) value of 0.579 and an r(2) value of 0.970, in which the good correlation between the MetRS inhibitory activities (IC(50)) and the steric and electrostatic molecular fields around the analogues was examined. Two inhibitors (1 and 17) were docked into the binding pocket of Escherichia coli MetRS imported from the X-ray crystal structure of the MetRS-methionine complex, and the details of their interaction with the amino acids of the active site are discussed.

Binding Sites↗
PubMed2006

Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA, and molecular docking.

In a continuing effort to develop highly potent azole antifungal agents, the three-dimensional quantitative structure-activity relationship methods, CoMFA and CoMSIA, were applied using a set of novel azole antifungal compounds. The binding mode of the compounds at the active site of lanosterol 14alpha-demethylase was further explored using the flexible docking method. Various hydrophobic, van der Waals, pi-pi stacking, and hydrogen bonding interactions were observed between the azoles and the enzyme. Based on results from the molecular modeling, a receptor-based pharmacophore model was established to guide the rational optimization of the azole antifungal agents. Thus, a total of 57 novel azoles were designed and synthesized by a three-step optimization process. In vitro antifungal assay revealed that the antifungal activities of these novel azoles were greatly improved, which confirmed the reliability of the model from molecular modeling.

Antifungal Agents↗
PubMed2004

Interaction of noncompetitive inhibitors with an immobilized alpha3beta4 nicotinic acetylcholine receptor investigated by affinity chromatography, quantitative-structure activity relationship analysis, and molecular docking.

A large number of drug substances act as noncompetitive inhibitors (NCIs) of the nicotinic acetylcholine receptor (nAChR) by blocking the ion flux through the channel. An affinity chromatography technique has been developed for investigating the interactions between NCIs and the alpha3beta4 subtype of neuronal nAChR. The data obtained from the chromatographic study were used to construct QSAR models of the NCI-nAChR binding with both electronic and steric parameters observed as important descriptors. A molecular model of the transmembrane domain of the alpha3beta4 subtype of nAChR was constructed and used to simulate the docking of a series of NCIs. A key aspect of the model was the discovery of the cleft produced by the incorporation of the bulky phenylalanine moiety into the nonpolar section of the lumen by the beta4 subunit. Quantitatively, the results of docking simulations modeled the experimental affinity data better than QSAR results. The computational approach, combined with the modeling of NCI-nAChR interaction by affinity chromatography, can be used to predict possible toxicities and adverse interactions.

Amino Acid Sequence↗
PubMed2003

Construction and assessment of models of CYP2E1: predictions of metabolism from docking, molecular dynamics, and density functional theoretical calculations.

3D models of CYP2E1 were constructed for the purpose of structure-based prediction of 2E1 metabolism of diverse substrates based on configuration sampling of ligand-atom-oxyferryl center distances and quantum chemical criteria. Models were constructed on the basis of sequence alignments of 2E1 with templates of known structure, including rabbit CYP2C5 (3LVdH) and bacterial CYP450s. Following geometric and energetic assessments, the utility of the model was tested in structure-based predictions of metabolism. Autodock was used to dock chlorzoxazone, p-nitrophenol, N-nitrosodimethylamine, acetominophen, caffeine, theophylline, and methoxyflurane into the model CYP2E1 employing a model oxyferryl heme with charges based on density functional theoretical parametrization. In all cases, the lowest energy bound docked configurations corresponded to ones with the substrate intimately associated with the oxyferryl center. Configurations among the lowest energy docked forms of each of the ligands had orientations relative to the oxyferryl center consistent with the experimentally observed metabolites. Docking of long-chain dialkylnitrosoamines revealed no heme binding site bound configurations, in agreement with the negligible metabolism of these ligands. The lowest energy docked configurations of chlorzoxazone, p-nitrophenol, and N-nitrosodimethylamine, high-affinity substrates of 2E1, were used to initiate 300 ps molecular dynamics (MD) trajectories. The MD-sampled ligand-oxyferryl heme reactant configurations were in good accord with density functional theoretical (DFT) optimized oxyferryl-heme-ligand geometries. Analysis of the MD-sampled ligand-2E1 configurations from multiple docked orientations indicates the configurations with closest exposure of reactive centers to the oxyferryl heme to be correlated with observed metabolites with proper consideration of H-abstraction energetics. DFT assessment of relative radical energetics is directly compared with differential H-abstraction activation energetics by compound I and by a p-nitrosophenoxy radical compound I surrogate for the specific case of methoxyflurane and is shown to be in good agreement.

Amino Acid Sequence↗
PubMed2004

CoMFA, HQSAR and molecular docking studies of butitaxel analogues with beta-tubulin.

Results from biochemical analyses for a series of 20 butitaxel analogues, paclitaxel and docetaxel were used to build two- and three-dimensional quantitative structure-activity relationship (QSAR) models in order to investigate the properties associated with microtubule assembly and stabilization. A comparative molecular field analysis (CoMFA) model was built using steric and electrostatic fields. The CoMFA model yielded an r2 of 0.943 and a cross-validated r2 (i.e. q2) of 0.376. Hologram quantitative structure-activity relationship (HQSAR) modeling of these same data generated an r2 of 0.919 and a q2 of 0.471. Contour maps used to visualize the steric and electrostatic contributions associated with activity or lack thereof were, as expected, localized to the varied position of the taxane system. Each analogue was docked successfully into a model of beta-tubulin derived from previously determined cryoelectron microscopy analyses of the tubulin alpha/beta heterodimer. All analogues superimposed well with paclitaxel bound to the protein, as well as with each other. Defining the variable region of each structure as the ligand and docking it separately into the paclitaxel site revealed a modest correlation (r2 = 0.53) between activity and docking energy of all the compounds in the dataset. When only the butitaxel derivatives were considered, the correlation increased to 0.61. The mathematical models derived here provide information for the future development of taxanes.

Animals↗