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Results for “molecular docking studies”

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PubMedDate not supplied

Ionization state and molecular docking studies for the macrophage migration inhibitory factor: the role of lysine 32 in the catalytic mechanism.

The macrophage migration inhibitory factor (MIF) is a cytokine that is structurally similar to certain isomerases and for which multiple immune and catalytic roles have been proposed. Different catalytic activities have been reported for MIF, yet the exact mechanism by which MIF acts is not completely known. As a tautomerase, the enzyme uses a general acid-base mechanism of proton transfer in which the amino-terminal proline has been shown to function as the catalytic base. We report the results of molecular docking simulations of macrophage migration inhibitory factor with three substrates, D-dopachrome, L-dopachrome methyl ester and p-(hydroxyphenyl)pyruvate. Electrostatic pK(a) predictions were also performed for the free and complexed forms of the enzyme. The predicted binding mode of p-(hydroxyphenyl)pyruvate is in agreement with the recently published X-ray structure. A model for the binding mode of D-dopachrome and L-dopachrome methyl ester to MIF is proposed which offers insights into the catalytic mechanism of D-dopachrome tautomerase activity of MIF. The proposed catalytic mechanism is further supported by the pK(a) predictions, which suggest that residue Lys32 acts as the general acid for the enzymatic catalysis of D-dopachrome.

Catalysis↗

PubMed2006

Homology modeling and molecular docking study of translationally controlled tumor protein and artemisinin.

Translationally controlled tumor protein (TCTP), also known as histamine releasing factor (HRF), is found abundantly in different eukaryotic cell types. The sequence homology of TCTP between different species is very high, belonging to the MSS4/DSS4 superfamily of proteins. TCTP is involved in both cell growth and human late allergy reaction, as well as having a calcium binding property; however, its primary biological functions remain to be clearly elucidated. In regard to many possible functions, the TCTP of Plasmodium falciparum (Pf) is known to bind with an antimalarial agent, artemisinin, which is activated by heme. It is assumed that the endoperoxide-bridge of artemisinin is opened up by heme to form a free radical, which then eventually alkylates, probably to the Cys14 of PfTCTP. Study of the docking of artemisinin with heme, and subsequently with PfTCTP, was carried out to verify the above hypothesis on the basis of structural interactions. The three dimensional (3D) structure of PfTCTP was built by homology modeling, using the NMR structure of the TCTP of Schizosaccharomyces pombe as a template. The quality of the model was examined based on its secondary structure and biological function, as well as with the use of structure evaluating programs. The interactions between artemisinin, heme and PfTCTP were then studied using the docking program, FlexiDock. The center of the peroxide bond of artemisinin and the Fe of heme were docked within a short distance of 2.6A, implying the strong possibility of an interaction between the two molecules, as proposed. When the activated form of artemisinin was docked on the PfTCTP, the C4-radical of the drug faced towards the sulfur of Cys14 within a distance of 2.48A, again suggesting the possibility of alkylation having occurred. These results confirm the proposed mechanism of the antimalarial effect of artemisinin, which will provide a reliable method for establishing the mechanism of its biological activity using a molecular modeling study.

Antimalarials↗

PubMed1999

Molecular docking studies on interaction of diverse retinol structures with human alcohol dehydrogenases predict a broad role in retinoid ligand synthesis.

Some members of the human alcohol dehydrogenase (ADH) family possess retinol dehydrogenase activity and may thus function in production of the active nuclear receptor ligand retinoic acid. Many diverse natural forms of retinol exist including all-trans-retinol (vitamin A(1)), 9-cis-retinol, 3,4-didehydroretinol (vitamin A(2)), 4-oxo-retinol, and 4-hydroxy-retinol as well as their respective carboxylic acid derivatives which are active ligands for retinoid receptors. This raises the question of whether ADHs can accommodate all these different retinols and thus participate in the activation of several retinoid ligands. The crystal structures of human ADH1B and ADH4 provide the opportunity to examine their active sites for potential binding to many diverse retinol structures using molecular docking algorithms. The criteria used to score successful docking included achievement of distances of 1.9-2.4 A between the catalytic zinc and the hydroxyl oxygen of retinol and 3.2-3.6 A between C-4 of the coenzyme NAD and C-15 of retinol. These distances are sufficient to enable hydride transfer during the oxidation of an alcohol to an aldehyde. By these criteria, all-trans-retinol, 4-oxo-retinol, and 4-hydroxy-retinol were successfully docked to both ADH1B and ADH4. However, 9-cis-retinol and 3,4-didehydroretinol, which have more restrictive conformations, were successfully docked to only ADH4 which possesses a wider active site than ADH1B and more easily accommodates the C-19 methyl group. Furthermore, docking of all retinols was more favorable in the active site of ADH4 rather than ADH1B as measured by force field and contact scores. These findings suggest that ADH1B has a limited capacity to metabolize retinols, but that ADH4 is well suited to function in the metabolism of many diverse retinols and is predicted to participate in the synthesis of the active ligands all-trans-retinoic acid, 9-cis-retinoic acid, 3, 4-didehydroretinoic acid, 4-oxo-retinoic acid, and 4-hydroxy-retinoic acid.

Alcohol Dehydrogenase↗

PubMed1998

Sequence-alignment modelling and molecular docking studies of the epoxygenase component of alkene monooxygenase from Nocardia corallina B-276.

Whole cells of Nocardia corallina B-276 catalyse the stereoselective epoxygenation of alkenes to chiral epoxides. The bacterium expresses an enzyme, alkene monooxygenase, which catalyses the epoxygenation reaction stereoselectively. The enzyme consists of a terminal oxygenase (epoxygenase), an NADH-dependent reductase (reductase) and a regulatory component (coupling protein). The epoxygenase component contains a bridged diiron centre similar to that found in the hydroxylase component of soluble methane monooxygenase. Sequence-alignment modelling, supported by chemical modification and fluorescence probing, identified a hydrophobic oxygen/substrate binding site within the epoxygenase. The diiron centre was coordinated by the two His and two Glu residues from two conserved Glu-Xaa-Xaa-His sequences and by two further Glu residues. Molecular docking of substrates and products into the proposed active-site model of the epoxygenase suggested that Ala91 and Ala185 were responsible for the stereoselectivity exerted by AMO. It is proposed that these residues clamped the intermediate and/or product of the reaction, thereby controlling the configuration of the epoxide produced. In soluble methane monooxygenase these residues are replaced by two Gly residues which do not provide sufficient steric hindrance to prevent rotation of the intermediate in the active site and, therefore, the product of the reaction catalysed by this enzyme is achiral.

Amino Acid Sequence↗

PubMed2003

Molecular docking studies of natural cholinesterase-inhibiting steroidal alkaloids from Sarcococca saligna.

Alkaloids isolated from Sarcococca saligna significantly inhibit acetyl- and butyrylcholinesterase enzyme, suggesting discovery of inhibitors for nervous-system disorders. Studying interactions with the active site of the AChE enzyme from Torpedo californica, we have identified hydrophobic interactions inside the aromatic gorge area as the major stabilizing factor in enzyme-inhibitor complexes of these alkaloids. Molecular Dynamics simulation of a predicted complex indicates that ligand binding does not extensively alter enzyme structure, but reduces flexibility at the gorge.

Acetylcholinesterase↗

PubMed2006

Molecular docking studies on 4-thiazolidinones as HIV-1 RT inhibitors.

Flexible docking simulations were performed on two series of 4-thiazolidinones as HIV-1 reverse transcriptase (HIV-1 RT) inhibitors. This was done by analyzing the interaction of these compounds with the allosteric site of the HIV-1 reverse transcriptase enzyme. The binding scores for these compounds were also congruent with their anti-HIV activity. A good correlation between the predicted binding free energies and the experimentally observed inhibitory activities (EC(50)) suggest that the identified binding conformations of these inhibitors are reliable. The results of docking studies provide an insight into the pharmacophoric structural requirements for the HIV-1 RT inhibitory activity of this class of molecules.

Allosteric Site↗

PubMed2005

Molecular docking study on the "back door" hypothesis for product clearance in acetylcholinesterase.

Acetylcholinesterase (AChE) is one of the fastest enzymes known, even though the active site is buried inside the protein at the end of a 20-A deep narrow gorge. Among the great variety of crystal structures of this enzyme, both in the absence and presence of various ligands and proteins, the structure of a complex of AChE with the pseudo-irreversible inhibitor Mf268 is of particular interest, as it assists in the proposal of a back door for product clearance from the active site. Binding of Mf268 to AChE results in the carbamoylation of Ser200 and liberation of an eseroline-fragment as the leaving group. The crystal structure of the AChE-Mf268 complex, however, proves that eseroline has escaped from the enzyme, despite the fact that the Ser-bound inhibitor fragment blocks the gorge entrance. The existence of alternative routes other than through the gorge for product clearance has been postulated but is still controversially discussed in the literature, as an experimental proof for such a back door is still missing. We have used Monte Carlo-based molecular docking methods in order to examine possible alternative pathways that could allow eseroline to be released from the protein after being cleaved from the substrate by Ser200. Based on our results, a short channel at the bottom of the gorge seems to be the most probable back-door site, which begins at amino acid Trp84 and ends at the enzyme surface in a cavity close to amino acid Glu445. [Figure: see text].

Acetylcholinesterase↗

PubMed2004

Performance of 3D-database molecular docking studies into homology models.

The performance of docking studies into protein active sites constructed by homology model building was investigated using CDK2 and factor VIIa screening data sets. When the sequence identity between model and template near the binding site area is greater than approximately 50%, roughly 5 times more active compounds are identified than would be found randomly. This performance is comparable to docking to crystal structures.

Binding Sites↗

PubMed2006

Specificity of Prodan for the self-associating domain of spectrin: a molecular docking study.

The hydrophobic fluorescent probe Prodan binds to the self-associating domain of spectrin with 1:1 stoichiometry. A model of the self-associating domain was generated based on its homology with other domains of spectrin. Prodan was then docked onto the model, and several sites with low interaction energy were identified. To verify whether the binding of Prodan is specific towards the self-associating domain of spectrin, it was docked on to several other domains of spectrin, having a known three-dimensional structure. Analysis of the docking results suggests that the binding of Prodan to the self-associating domain of spectrin will involve hydrophobic and hydrophilic groups of Prodan. The results clearly indicate the preference of Prodan for a particular binding site of the self-associating domain.

Amino Acid Sequence↗

PubMed2006

3D-QSAR and molecular docking studies on pyrazolopyrimidine derivatives as glycogen synthase kinase-3beta inhibitors.

Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is a fascinating enzyme with diverse biological actions in intracellular signaling systems, making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar disorders and Alzheimer's disease. It is important to inhibit GSK-3 selectively and the net effect of the GSK-3 inhibitors thus should be target specific, over other phylogenetically related kinases such as CDK-2. In the present work, we have carried out three-dimensional quantitative structure activity relationship (3D-QSAR) studies on novel class of pyrazolopyrimidine derivatives as GSK-3 inhibitors reported to have improved cellular activity. Docked conformation of the most active molecule in the series, which shows desirable interactions in the receptor, was taken as template for alignment of the molecules. Statistically significant CoMFA and CoMSIA models were generated using 49 molecules in training set. By applying leave-one-out (LOO) cross-validation study, r(cv)2 values of 0.53 and 0.48 for CoMFA and CoMSIA, respectively and non-cross-validated (r(ncv)2) values of 0.98 and 0.92 were obtained for CoMFA and CoMSIA models, respectively. The predictive ability of CoMFA and CoMSIA models was determined using a test set of 12 molecules which gave predictive correlation coefficients (r(pred)2) of 0.47 and 0.48, respectively, indicating good predictive power. Based upon the information derived from CoMFA and CoMSIA contour maps, we have identified some key features that explain the observed variance in the activity and have been used to design new pyrazolopyrimidine derivatives. The designed molecules showed better binding affinity in terms of estimated docking scores with respect to the already reported systems; hence suggesting that newly designed molecules can be more potent and selective towards GSK-3beta inhibition.

Binding, Competitive↗

PubMed2025

Inflammatory pathways and immune dysregulation in pediatric postoperative septic shock: A study integrating transcriptomics, machine learning and molecular docking.

This study elucidates the molecular and immune regulatory mechanisms of pediatric postoperative septic shock. Transcriptomic data were obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified using the limma package, and gene co-expression modules were constructed using Weighted Gene Co-expression Network Analysis. Functional enrichment was performed via gene set enrichment analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. Immune cell infiltration was assessed using ESTIMATE and CIBERSORT. Mendelian randomization was applied to explore causal relationships between gene expression and septic shock. Feature genes were selected using machine learning algorithms, and a diagnostic nomogram model was constructed. Finally, molecular docking analysis was performed to screen and evaluate the binding affinity of traditional Chinese medicine monomers to core target proteins. A total of 1331 differentially expressed genes were identified, and the turquoise module was strongly correlated with septic shock. Enrichment analysis revealed significant activation of IL-6/JAK/STAT3, TNF-α/NF-κB, and PI3K/Akt/mTOR pathways. Immune infiltration analysis indicated suppressed immune scores and imbalances in neutrophils, macrophages, T cells, and B cells. Mendelian randomization confirmed causal associations for 6 genes, including PIM3. The predictive model based on feature genes demonstrated high diagnostic performance. Molecular docking suggested that quercetin and astramembrannin I could stably bind PIM3. This study systematically identified core genes, dysregulated immune pathways, and candidate small-molecule interventions in pediatric septic shock, providing novel insights for early diagnosis and targeted therapy.

Humans↗

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↗

PubMed2003

Plausible interaction of an alpha-fetoprotein cyclopeptide with the G-protein-coupled receptor model GPR30: docking study by molecular dynamics simulated annealing.

In this manuscript, the procedure of molecular dynamics simulated annealing is applied to locate a probable receptor and binding site of a cyclicpeptide that inhibits estrogen-stimulated proliferation of breast cancer. The hydrophilic cyclopeptide EMTOVNOGQ (O = 4-hydroxyproline), derived from alpha-fetoprotein, is an inhibitor of estrogen-stimulated proliferation of human breast cancer. This peptide has been shown to act through a mechanism different from that of estrogen; however, its receptor is unknown. We report computer experiments that suggest that this peptide may execute its actions by interacting with GPR30, a G-protein-coupled receptor. The subject of this work is the simulation, by molecular dynamics simulated annealing, of the interaction of cyclopeptide EMTOVNOGQ with receptor GPR30 protein. A conformational analysis of the cyclopeptide was undertaken and the final structure was docked on several sites of the GPR30 3D model. Our results show that the cyclopeptide interacts on the pocket located between TM6 and TM7 transmembrane helices of the G-protein, triggering a slight conformational change in the secondary structure of the receptor in the complex. Based on differences in accessible surface areas between GPR30 and its ligand, the residues in the interaction zone were identified. The cyclopeptide is stabilized in the active site by forming a network of hydrogen bonds between Glu, Thr, (1)Pro(OH) and GLn residues of the ligand and Arg-259, Cys-271, Asn-316, Asn-320 and Tyr-324 of the G-protein. Moreover, the study of the electrostatic surface potential on the GPR30 receptor shows that the active site is more positively charged than the other sites. Our modeling indicates a plausible interaction of the cyclopeptide with the seven transmembrane GPR30 protein. This may have profound implications for the treatment of breast cancer.

Amino Acid Sequence↗

PubMed2006

Identification of the binding region of the [2Fe-2S] ferredoxin in stearoyl-acyl carrier protein desaturase: insight into the catalytic complex and mechanism of action.

Stearoyl-acyl carrier protein desaturase (Delta9D) catalyzes the O(2) and 2e(-) dependent desaturation of stearoyl-acyl carrier protein (18:0-ACP) to yield oleoyl-ACP (18:1-ACP). The 2e(-) are provided by essential interactions with reduced plant-type [2Fe-2S] ferredoxin (Fd). We have investigated the protein-protein interface involved in the Fd-Delta9D complex by the use of chemical cross-linking, site-directed mutagenesis, steady-state kinetic approaches, and molecular docking studies. The treatment of the different proteins with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide revealed that carboxylate residues from Fd and lysine residues from Delta9D contribute to cross-linking. The single substitutions of K60A, K56A, and K230A on Delta9D decreased the k(cat)/K(M) for Fd by 4-, 22-, and 2400-fold, respectively, as compared to wt Delta9D and a K41A substitution. The double substitution K56A/K60A decreased the k(cat)/K(M) for Fd by 250-fold, whereas the triple mutation K56A/K60A/K230A decreased the k(cat)/K(M) for Fd by at least 700 000-fold. These results strongly implicate the triad of K56, K60, and K230 of Delta9D in the formation of a catalytic complex with Fd. Molecular docking studies indicate that electrostatic interactions between K56 and K60 and the carboxylate groups on Fd may situate the [2Fe-2S] cluster of Fd closer to W62, a surface residue that is structurally conserved in both ribonucleotide reductase and mycobacterial putative acyl-ACP desaturase DesA2. Owing to the considerably larger effects on catalysis, K230 appears to have other contributions to catalysis arising from its positioning in helix 7 and its close spatial location to the diiron center ligands E229 and H232. These results are considered in the light of the presently available models for Fd-mediated electron transfer in Delta9D and other protein-protein complexes.

Binding Sites↗

PubMed2005

Toward selective histone deacetylase inhibitor design: homology modeling, docking studies, and molecular dynamics simulations of human class I histone deacetylases.

Histone deacetylases (HDACs) play an important role in gene transcription. Inhibitors of HDACs induce cell differentiation and suppress cell proliferation in tumor cells. Although many HDAC inhibitors have been designed and synthesized, selective inhibition for class I HDAC isoforms is a goal that has yet to be achieved. To understand the difference between class I HDAC isoforms that could be exploited for the design of isoform-specific HDAC inhibitors, we have built three-dimensional models of four class I histone deacetylases, HDAC1, HDAC2, HDAC3, and HDAC8. Comparison of the homology model of HDAC8 with the recently published X-ray structure shows excellent agreement and validates the approach. A series of HDAC inhibitors were docked to the homology models to understand the similarities and differences between the binding modes. Molecular dynamic simulations of these HDAC-inhibitor complexes indicate that the interaction between the protein surface and inhibitor is playing an important role; also some active site residues show some flexibility, which is usually not included in routine docking protocols. The implications of these results for the design of isoform-selective HDAC inhibitors are discussed.

Amino Acid Sequence↗

PubMed2026

Elucidating the Mechanism of Xiaoqinglong Decoction in Chronic Urticaria Treatment: An Integrated Approach of Network Pharmacology, Bioinformatics Analysis, Molecular Docking, and Molecular Dynamics Simulations.

INTRODUCTION: Xiaoqinglong Decoction (XQLD) is a traditional Chinese medicinal formula commonly used to treat chronic urticaria (CU). However, its underlying therapeutic mechanisms remain incompletely characterized. This study employed an integrated approach combining network pharmacology, bioinformatics, molecular docking, and molecular dynamics simulations to identify the active components, potential targets, and related signaling pathways involved in XQLD's therapeutic action against CU, thereby providing a mechanistic foundation for its clinical application. METHODS: The active components of XQLD and their corresponding targets were identified using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. CU-related targets were retrieved from the OMIM and GeneCards databases. Subsequently, core components and targets were determined via protein-protein interaction (PPI) network analysis and component-target-pathway network construction. Topological analyses were performed using Cytoscape software to prioritize core nodes within these networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via the DAVID database to identify enriched biological processes and signaling pathways. Molecular docking was performed to evaluate binding interactions between key components and core targets, while molecular dynamics (MD) simulations were employed to assess the stability of the component-target complexes with the lowest binding energy. Finally, CU-related targets of XQLD were validated using datasets from the Gene Expression Omnibus (GEO) database. RESULTS: A total of 135 active components and 249 potential targets of XQLD were identified, alongside 1,711 CU-related targets. Core components, such as quercetin, kaempferol, beta-sitosterol, naringenin, stigmasterol, and luteolin, exhibited high degree values in the constructed networks. The core targets identified included AKT1, TNF, IL6, TP53, PTGS2, CASP3, BCL2, ESR1, PPARG, and MAPK3. GO and KEGG pathway enrichment analyses revealed the PI3K-Akt signaling pathway as a central regulatory mechanism. Molecular docking studies demonstrated strong binding affinities between active components and core targets, with the stigmasterol-AKT1 complex exhibiting the lowest binding energy (-11.4 kcal/mol) and high stability in MD simulations. Validation using GEO datasets identified 12 core genes shared between CU-related targets and XQLD-associated targets, including PTGS2 and IL6, which were also prioritized as core targets in the network pharmacology analyses. DISCUSSION: This study comprehensively integrates multidisciplinary approaches to clarify the potential molecular mechanisms of XQLD in treating CU, highlighting its multitarget and multipathway synergistic effects. Molecular docking and dynamics simulations confirm the stable interaction between stigmasterol and the core target AKT1. Additionally, GEO dataset analysis verifies the pathogenic relevance of targets such as PTGS2 and IL6, significantly enhancing the credibility of our findings. These results provide a modern scientific basis for the traditional therapeutic effects of XQLD on CU and have important implications for developing multitarget treatments for this condition. However, this study mainly relies on database mining and computational simulations. Further in vitro and in vivo experimental validations are needed to confirm the predicted component-target-pathway interactions. CONCLUSION: This study identifies the active components, potential targets, and pathways through which XQLD exerts therapeutic effects on CU. These findings provide a theoretical foundation for further mechanistic studies and support their clinical application in the treatment of CU.

Molecular Docking Simulation↗

PubMed2004

Prediction of HIV-1 integrase/viral DNA interactions in the catalytic domain by fast molecular docking.

This study details the separate analyses of binding specificity of HIV-1 integrase (IN) and viral B-DNA forms through ligand-receptor docking studies by means of a fast molecular docking method. The application of solvated electrostatics with the University of Houston Brownian Dynamics Program (UHBD) and configurational sampling by the Daughter of Turnip (DOT) docking program resulted in the computation of energies of more than 113 billion configurations for each ligand-receptor docking study, a procedure considered computationally intractable a few years ago. A specific binding pattern of viral DNA to the IN catalytic domain region has been predicted as a result of these calculations. In a representative docked configuration, we observe the 3'-hydroxyl of the conserved deoxyadenosine to be close to one of the two divalent metal ions that are necessary for catalysis. A superimposition of our energy-minimized docked complex on representative structures from a molecular dynamics (MD) simulation of a crystallographically resolved IN/inhibitor complex revealed an overlap of viral DNA with the inhibitor, indicating that the bound inhibitor might operate by blocking substrate binding. The DOT docking calculation also identified a second, adjacent DNA-binding site, which we believe is the nonspecific host DNA binding site. The binding pattern predicted by DOT complements previous electrostatics, MD simulation, photo-cross-linking, and mutagenesis studies and also provides a further refinement of the IN/viral DNA binding interaction as a basis for new structure-based design efforts.

Catalytic Domain↗

PubMed2005

Application of molecular modeling to analysis of inhibition of kinesin motor proteins of the BimC subfamily by monastrol and related compounds.

Application of molecular modeling approaches has potential to contribute to rational drug design. These approaches may be especially useful when attempting to elucidate the structural features associated with novel drug targets. In this study, molecular docking and molecular dynamics were applied to studies of inhibition of the human motor protein denoted HsEg5 and other homologues in the BimC subfamily. These proteins are essential for mitosis, so compounds that inhibit their activity may have potential as anticancer therapeutics. The discovery of a small-molecule cell-permeable inhibitor, monastrol, has stimulated research in this area. Interestingly, monastrol is reported to inhibit the human and Xenopus forms of Eg5, but not those from Drosophila and Aspergillus. In this study, homology modeling was used to generate models of the Xenopus, Drosophila, and Aspergillus homologues, using the crystal structure of the human protein in complex with monastrol as a template. A series of known inhibitors was docked into each of the homologues, and the differences in binding energies were consistent with reported experimental data. Molecular dynamics revealed significant changes in the structure of the Aspergillus homologue that may contribute to its relative insensitivity to monastrol and related compounds.

Animals↗