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Results for “Molecular Docking Simulation”

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PubMed2005

Integrated Modeling Program, Applied Chemical Theory (IMPACT).

We provide an overview of the IMPACT molecular mechanics program with an emphasis on recent developments and a description of its current functionality. With respect to core molecular mechanics technologies we include a status report for the fixed charge and polarizable force fields that can be used with the program and illustrate how the force fields, when used together with new atom typing and parameter assignment modules, have greatly expanded the coverage of organic compounds and medicinally relevant ligands. As we discuss in this review, explicit solvent simulations have been used to guide our design of implicit solvent models based on the generalized Born framework and a novel nonpolar estimator that have recently been incorporated into the program. With IMPACT it is possible to use several different advanced conformational sampling algorithms based on combining features of molecular dynamics and Monte Carlo simulations. The program includes two specialized molecular mechanics modules: Glide, a high-throughput docking program, and QSite, a mixed quantum mechanics/molecular mechanics module. These modules employ the IMPACT infrastructure as a starting point for the construction of the protein model and assignment of molecular mechanics parameters, but have then been developed to meet specialized objectives with respect to sampling and the energy function.

Computer Simulation↗

PubMed1999

Flexible ligand docking: a multistep strategy approach.

A flexible ligand docking protocol based on a divide-and-conquer strategy is investigated. This approach first separates total search space into conformation and orientation space. It uses a grid-based method to sample the conformation of an unbound ligand and to select the low-energy conformers. Rigid docking is then carried out to locate the low-energy binding orientations for these conformers. These docking structures are subsequently subjected to structure refinement including molecular mechanics minimization, conformational scanning at the binding site and a short period of molecular dynamics-based simulated annealing. This approach has been applied to twelve ligand-protein complexes with three to sixteen rotatable bonds. The docked lowest-energy structures have root mean square deviations ranging from 0.64 A to 2.01 A with respect to the corresponding crystal structures. The effect of atomic charges and van der Waals parameters on the docking results, and the role of the dielectric constant in the conformation sampling are discussed in detail. A fragment-based docking approach that takes advantages of the divide-and-conquer strategy has also been explored and the results are compared with those produced by a whole molecule-based approach.

Hydrogen Bonding↗

PubMed1998

Structure prediction of a complex between the chromosomal protein HMG-D and DNA.

Non-histone chromosomal proteins are an important part of nuclear structure and function due to their ability to interact with DNA to form and modulate chromatin structure and regulate gene expression. However, the understanding of the function of chromosomal proteins at the molecular level has been hampered by the lack of structures of chromosomal protein-DNA complexes. We have carried out a molecular dynamics modeling study to provide insight into the mode of DNA binding to the chromosomal HMG-domain protein, HMG-D. Three models of a complex of HMG-D bound to DNA were derived through docking the protein to two different DNA fragments of known structure. Molecular dynamics simulations of the complexes provided data indicating the most favorable model. This model was further refined by molecular dynamics simulation and extensively analyzed. The structure of the corresponding HMG-D-DNA complex exhibits many features seen in the NMR structures of the sequence-specific HMG-domain-DNA complexes, lymphoid enhancer factor 1 (LEF-1) and testis determining factor (SRY). The model reveals differences from these known structures that suggest how chromosomal proteins bind to many different DNA sequences with comparable affinity.

Amino Acid Sequence↗

PubMed1991

Molecular dynamics of dopamine at the D2 receptor.

A three-dimensional model of the dopamine D2 receptor, assumed to be a target of antipsychotic drug action, was constructed from its amino acid sequence. The model was based on structural similarities within the super-family of guanine nucleotide-binding regulatory (G) protein-coupled neuroreceptors and has seven alpha-helical transmembrane segments that form a central core with a putative ligand-binding site. The space between two residues postulated to be involved in agonist binding, Asp-80 and Asn-390, perfectly accommodated an anti-dopamine molecule. Molecular electrostatic potentials were mainly negative on the synaptic side of the receptor model and around aspartate residues lining the central core and positive in the cytoplasmic domains. The docking of dopamine into a postulated binding site was examined by molecular dynamics simulation. The protonated amino group became oriented toward negatively charged aspartate residues in helix 2 and helix 3, whereas the dopamine molecule fluctuated rapidly between different anti and gauche conformations during the simulation. The receptor model suggests that protonated ligands are attracted to the binding site by electrostatic forces and that protonated agonists may induce conformational changes in the receptor, leading to G-protein activation, by increasing the electrostatic potentials near Asp-80.

Amino Acid Sequence↗

PubMed2026

Comparative and Subtractive Genomics Analysis of Multidrug-Resistant Klebsiella pneumoniae Strains for Novel Target Identification and Drug Repurposing Strategies.

The rapid rise of multidrug-resistant (MDR) Klebsiella pneumoniae has created a major global health challenge due to the limited availability of conserved therapeutic targets effective across diverse resistant strains. In this study, an integrative computational target-discovery and drug-repurposing framework was applied to six clinically relevant K. pneumoniae strains. Comparative genomic analysis identified 3012 conserved genes, which were subsequently filtered to nine essential, non-host homologous proteins. Among these, three conserved cytoplasmic proteins (accD, cpxR, and mraZ) were prioritized for functional analysis, with acetyl-CoA carboxylase subunit beta (accD) emerging as the most promising therapeutic target based on sequence conservation, predicted essentiality, subcellular localization, and pathway association. Structural assessment supported the reliability of the predicted accD model, whereas consensus binding-site analysis identified key residues suitable for ligand interaction. Virtual screening of FDA-approved drugs followed by molecular docking identified several compounds with favorable binding profiles toward accD. Subsequent molecular dynamics simulations, including root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), hydrogen-bond occupancy, principal component analysis (PCA), and PCA-based free energy landscape (FEL) analyses, consistently identified tenapanor, micafungin, deferoxamine, and cobicistat as the most stable protein-ligand complexes, with tenapanor exhibiting the most favorable overall structural and thermodynamic stability profile. These findings identify accD as a promising therapeutic target in MDR K. pneumoniae and suggest several FDA-approved compounds as potential candidates for drug repurposing. Although experimental validation is needed to confirm their biological activity and therapeutic potential, this study demonstrates the potential of integrating comparative genomics with molecular dynamics analyses to support antimicrobial target identification and drug repurposing against MDR bacterial pathogens.

Klebsiella pneumoniae↗

PubMed2006

Acetylcholinesterase: molecular modeling with the whole toolkit.

Molecular modeling efforts aimed at probing the structure, function and inhibition of the acetylcholinesterase enzyme have abounded in the last decade, largely because of the system's importance to medical conditions such as myasthenia gravis, Alzheimer's disease and Parkinson's disease, and well as its famous toxicological susceptibility to nerve agents. The complexity inherent in such a system with multiple complementary binding sites, critical dynamic effects and intricate mechanisms for enzymatic function and covalent inhibition, has led to an impressively diverse selection of simulation techniques being applied to the system, including quantum chemical mechanistic studies, molecular docking prediction of noncovalent complexes and their associated binding free energies, molecular dynamics conformational analysis and transport kinetics prediction, and quantitative structure activity relationship modeling to tie salient details together into a coherent predictive tool. Effective drug and prophylaxis design strategies for a complex target like this requires some understanding and appreciation for all of the above methods, thus it makes an excellent case study for multi-tiered pharmaceutical modeling. This paper reviews a sample of the more important studies on acetylcholinesterase and helps to elucidate their interdependencies. Potential future directions are introduced based on the special methodological needs of the acetylcholinesterase system and on emerging trends in molecular modeling.

Acetylcholinesterase↗

PubMed2002

Looking for selectivity among cytochrome P450s inhibitors.

Cytochrome P450s 19 and 17 are very important pharmacological targets in two different fields of cancer chemotherapy. We present here a theoretical study aimed at explaining the molecular basis of inhibitor affinity and selectivity for either P450 19 or P450 17. Docking simulations of two compounds pointed out the major physicochemical features associated with inhibitory activity. Our results, in agreement with site-directed mutagenesis experiments, could be of relevant utility when designing new P450 19 and P450 17 inhibitors.

Amino Acid Sequence↗

PubMed1998

The crystal structure of dienoyl-CoA isomerase at 1.5 A resolution reveals the importance of aspartate and glutamate sidechains for catalysis.

BACKGROUND: The degradation of unsaturated fatty acids is vital to all living organisms. Certain unsaturated fatty acids must be catabolized via a pathway auxiliary to the main beta-oxidation pathway. Dienoyl-coenzyme A (dienoyl-CoA) isomerase catalyzes one step of this auxiliary pathway, the isomerization of 3-trans,5-cis-dienoyl-CoA to 2-trans,4-trans-dienoyl-CoA, and is imported into both mitochondria and peroxisomes. Dienoyl-CoA isomerase belongs to a family of CoA-binding proteins that share the enoyl-CoA hydratase/isomerase sequence motif. RESULTS: The crystal structure of rat dienoyl-CoA isomerase has been determined at 1.5 A resolution. The fold closely resembles that of enoyl-CoA hydratase and 4-chlorobenzoyl-CoA dehalogenase. Dienoyl-CoA isomerase forms hexamers made up of two trimers. The structure contains a well ordered peroxisomal targeting signal type-1 which is mostly buried in the inter-trimer space. The active-site pocket is deeply buried and entirely hydrophobic, with the exception of the acidic residues Asp176, Glu196 and Asp204. Site-directed mutagenesis of Asp204 revealed that this residue is essential for catalysis. In a molecular modeling simulation, a molecule of 3-trans,5-cis-octadienoyl-CoA was docked into the active site. CONCLUSIONS: The structural data, supported by the mutagenesis data, suggest a reaction mechanism where Glu196 acts as a proton acceptor and Asp204 acts as a proton donor. Asp176 is paired with Glu196 and is important for optimizing the catalytic proton transfer properties of Glu196. In the predicted mode of substrate binding, an oxyanion hole stabilizes the transition state by binding the thioester oxygen. The presence of a buried peroxisomal targeting signal suggests that dienoyl-CoA isomerase is prevented from reaching its hexameric structure in the cytosol.

Acyl Coenzyme A↗

PubMed2002

Binding affinity prediction of novel estrogen receptor ligands using receptor-based 3-D QSAR methods.

We have recently reported the development of a 3-D QSAR model for estrogen receptor ligands showing a significant correlation between calculated molecular interaction fields and experimentally measured binding affinity. The ligand alignment obtained from docking simulations was taken as basis for a comparative field analysis applying the GRID/GOLPE program. Using the interaction field derived with a water probe and applying the smart region definition (SRD) variable selection procedure, a significant and robust model was obtained (q(2)(LOO)=0.921, SDEP=0.345). To further analyze the robustness and the predictivity of the established model several recently developed estrogen receptor ligands were selected as external test set. An excellent agreement between predicted and experimental binding data was obtained indicated by an external SDEP of 0.531. Two other traditionally used prediction techniques were applied in order to check the performance of the receptor-based 3-D QSAR procedure. The interaction energies calculated on the basis of receptor-ligand complexes were correlated with experimentally observed affinities. Also ligand-based 3-D QSAR models were generated using program FlexS. The interaction energy-based model, as well as the ligand-based 3-D QSAR models yielded models with lower predictivity. The comparison with the interaction energy-based model and with the ligand-based 3-D QSAR models, respectively, indicates that the combination of receptor-based and 3-D QSAR methods is able to improve the quality of prediction.

Binding Sites↗

PubMed2001

Molecular modelling of 17 alpha-hydroxylase-17,20-lyase.

New methods in treatment of hormone-dependent diseases like prostate or breast cancer have become a major subject in medical and pharmaceutical research. Because of the direct correlation of cancer growth and hormone concentration inhibition of hormone biosynthesis reveals a promising strategy in cancer therapy. The key enzyme of androgen biosynthesis is the cytochrome P450 system 17 alpha-hydroxylase-17,20-lyase. To gain deeper insights into the structure and function of this enzyme, whose crystal structure is still unknown we present in this paper a theoretical 3D-model of the human 17 alpha-hydroxylase-17,20-lyase. The model was built by homology modelling using the crystal structure of the P450 CYPeryF as a template. After energy minimisation followed by molecular dynamics simulation the refined model exhibits reasonable protein geometry and a good protein folding quality. For evaluation of protein stability the structure was subjected to molecular dynamics in a waterbox under almost physiological conditions using the GROMACS program. The protein structure and folding remains stable even after 300 ps of free molecular dynamics simulation. The calculation of interaction fields employing the program GRID was used to characterise the active site of the protein. Subsequent docking studies with the natural substrate pregnenolone and further molecular dynamics of the protein-substrate-complexes enabled us to propose a putative binding-site for the physiological substrates.

Amino Acid Sequence↗

PubMed2002

Combining NMR spectral and structural data to form models of polychlorinated dibenzodioxins, dibenzofurans, and biphenyls binding to the AhR.

A three-dimensional quantitative spectrometric data-activity relationship (3D-QSDAR) modeling technique which uses NMR spectral and structural information that is combined in a 3D-connectivity matrix has been developed. A 3D-connectivity matrix was built by displaying all possible assigned carbon NMR chemical shifts, carbon-to-carbon connections, and distances between the carbons. Two-dimensional 13C-13C COSY and 2D slices from the distance dimension of the 3D-connectivity matrix were used to produce a relationship among the 2D spectral patterns for polychlorinated dibenzofurans, dibenzodioxins, and biphenyls (PCDFs, PCDDs, and PCBs respectively) binding to the aryl hydrocarbon receptor (AhR). We refer to this technique as comparative structural connectivity spectral analysis (CoSCoSA) modeling. All CoSCoSA models were developed using forward multiple linear regression analysis of the predicted 13C NMR structure-connectivity spectral bins. A CoSCoSA model for 26 PCDFs had an explained variance (r2) of 0.93 and an average leave-four-out cross-validated variance (q(2)4) of 0.89. A CoSCoSA model for 14 PCDDs produced an r2 of 0.90 and an average leave-two-out cross-validated variance (q(2)2) of 0.79. One CoSCoSA model for 12 PCBs gave an r2 of 0.91 and an average q(2)2 of 0.80. Another CoSCoSA model for all 52 compounds had an r2 of 0.85 and an average q(2)2 of 0.52. Major benefits of CoSCoSA modeling include ease of development since the technique does not use molecular docking routines.

Algorithms↗

PubMed2005

Theoretical investigations of prostatic acid phosphatase.

The phosphotyrosyl protein phosphatase activity of prostatic acid phosphatase (PAP) has been well established. It has also been suggested that PAP partly regulates the activity of growth factor receptors by dephosphorylating the autophosphorylysable tyrosines in them. We studied the binding of the peptides from epidermal growth factor receptor (EGFR) and its homolog (ErbB-2), corresponding to their autophosphorylation sites, to PAP using theoretical modeling and molecular dynamics (MD) simulation methods. Nine different peptides, each with a phosphotyrosine residue, were docked on human PAP. The binding energies of these peptide-PAP complexes were calculated theoretically and compared to experimentally obtained affinities. The peptide Ace--DNLpYYWD--NH2 from ErbB-2(1197-1203) showed the most favorable free energy of binding when estimated theoretically. The results demonstrate that the presence of another tyrosine residue proximate to C-terminal of autophosphorylysable Tyr enhances the binding affinity considerably. The presence of a bulky group instead prevents the binding, as is observed in case of peptide Ace--NLYpYWDQ--NH2 which failed to bind, both in theoretical calculations and experiments. Thus we demonstarted that PAP could potentially bind to EGFR and Erbb-2 and dephosphorylate them. Thus it could be involved in the regulation of the function of such receptors. In addition, complexes of a peptide from AngiotensinII and phosphotyrosine(pY) with human PAP were also modeled. The effects of different protonation states of the titratable active site residues on ligand (pY) binding have also been investigated. For a favorable binding His12 and Asp258 should be neutral, His257 should be positively charged and the phosphate group of the ligand should be in PO(4) (3-) state. Furthermore, the analysis of protein motion as observed during simulations suggests the loop-loop contact in the PAP dimer to be of importance in cooperativity.

Acid Phosphatase↗

PubMed2004

X-ray structure of a membrane-bound beta-glycosidase from the hyperthermophilic archaeon Pyrococcus horikoshii.

The beta-glycosidase of the hyperthermophilic Archaeon Pyrococcus horikoshii is a membrane-bound enzyme with the preferred substrate of alkyl-beta-glycosides. In this study, the unusual structural features that confer the extreme thermostability and substrate preferences of this enzyme were investigated by X-ray crystallography and docking simulation. The enzyme was crystallized in the presence of a neutral surfactant, and the crystal structure was solved by the molecular replacement method and refined at 2.5 A. The main-chain fold of the enzyme belongs to the (betaalpha)8 barrel structure common to the Family 1 glycosyl hydrolases. The active site is located at the center of the C-termini of the barrel beta-strands. The deep pocket of the active site accepts one sugar unit, and a hydrophobic channel extending radially from there binds the nonsugar moiety of the substrate. The docking simulation for oligosaccharides and alkylglucosides indicated that alkylglucosides with a long aliphatic chain are easily accommodated in the hydrophobic channel. This sparingly soluble enzyme has a cluster of hydrophobic residues on its surface, situated at the distal end of the active site channel and surrounded by a large patch of positively charged residues. We propose that this hydrophobic region can be inserted into the membrane while the surrounding positively charged residues make favorable contacts with phosphate groups on the inner surface of the membrane. The enzyme could thus adhere to the membrane in the proximity of its glycolipid substrate.

Amino Acid Sequence↗

PubMed2002

Molecular modelling of the differential interaction between several non-steroidal anti-inflammatory drugs and human prostaglandin endoperoxide H synthase-2 (h-PGHS-2).

The prostaglandin endoperoxide H synthase-1 (PGHS-1) and prostaglandin endoperoxide H synthase-2 (PGHS-2) are the targets of non-steroidal anti-inflammatory drugs (NSAIDs). The high degree of selectivity for inhibition of PGHS-2 shown by certain compounds appears to stem from two mechanisms (time-dependent, time-independent inhibition) by which they interact with each isoform. Molecular models of the complexes between indomethacin, fenamates, 2-phenylpropionic acids and the selective cyclooxygenase-2 (COX-2) inhibitors, with the cyclooxygenase active site of human PGHS-2 have been built by combining homology modelling, conformational searching and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations combined with extended linear response calculations. The results allow us to identify regions of biological significance consistent with both X-ray crystallographic and kinetic results. The selective PGHS-2 inhibitors exploit the extra space of a side-pocket in the active site of PGHS-2 that is not found in PGHS-1. The results obtained point out a marked relationship between the experimental affinity and the electrostatic interaction energy alone for a series of NSAIDs. Analysis of the structural and the energetic data provides evidence supporting that network of hydrogen bonds between Tyr355, Glu524, Arg120 and Arg513 might be involved in mediating the binding of the time-dependent inhibitors of PGHS-2.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2005

Pyrazolo[3,4-c]pyridazines as novel and selective inhibitors of cyclin-dependent kinases.

Pyrazolopyridazine 1a was identified in a high-throughput screening carried out by BASF Bioresearch Corp. (Worcester, MA) as a potent inhibitor of CDK1/cyclin B and shown to have selectivity for the CDK family. Analogues of the lead compound have been synthesized and their antitumor activities have been tested. A molecular model of the complex between the lead compound and the CDK2 ATP binding site has been built using a combination of conformational search and automated docking techniques. The stability of the resulting complex has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues have been rationalized on the basis of the proposed binding mode for compound 1a. As a result of the SAR study, monofuryl 1o has been synthesized and is one of the most active compounds against CDK1 of this series.

Adenosine Triphosphate↗

PubMed2004

Synthesis and biological evaluation of analogues of butyrolactone I and molecular model of its interaction with CDK2.

A series of analogues of butyrolactone I, a natural product isolated from Aspergillus terreus that selectively inhibits the CDK2 and CDK1 kinases and that has been found to exhibit an interesting antiproliferative activity, have been synthesized. Its antitumor activity has been tested. Molecular models of the complex between butyrolactone I and the CDK2 active site have been built using a combination of conformational search and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues are rationalized based on the molecular models.

4-Butyrolactone↗

PubMed2006

Elucidation of chiral recognition processes of macrocyclic antibiotic vancomycin.

A theoretical investigation was carried out on the retention and separation of enantiomeric molecules including nonsteroidal anti-inflammatory drugs, anti-neoplastic compounds and N-derivatized amino acids by capillary electrophoresis using macrocyclic antibiotics, a new class of chiral selectors, as stationary phase. Firstly docking methods were used to study the enantiorecognition in chiral electrophoresis. The molecular dynamics simulations of the two diastereoisomer complexes were then performed in order to understand how these antibiotics recognize the enantiomers. Another approach was applied in this study to establish a quantitative structure-enantioselectivity relationship (QSER) model, able to describe the resolution of a series of chiral compounds in capillary electrophoresis using vancomycin as the resolving agent.

Anti-Bacterial Agents↗

PubMed1999

Molecular modeling of human P450c17 (17alpha-hydroxylase/17,20-lyase): insights into reaction mechanisms and effects of mutations.

P450c17 (17alpha-hydroxylase/17,20-lyase) catalyzes steroid 17alpha-hydroxylase and 17,20-lyase activities in the biosynthesis of androgens and estrogens. These two activities are differentially regulated in a tissue-specific and developmentally programmed manner. To visualize the active site topology of human P450c17 and to study the structural basis of its substrate specificity and catalytic selectivity, we constructed a second-generation computer-graphic model of human P450c17. The energetics of the model are comparable to those of the principal template of the model, P450BMP, as determined from its crystallographic coordinates. The protein structure analysis programs PROCHECK, WHATIF, and SurVol indicate that the predicted P450c17 structure is reasonable. The hydrophobic active site accommodates both delta4 and delta5 steroid substrates in a catalytically favorable orientation. The predicted contributions of positively charged residues to the redox-partner binding site were confirmed by site-directed mutagenesis. Molecular dynamic simulations with pregnenolone, 17-OH-pregnenolone, progesterone, and 17-OH-progesterone docked into the substrate-binding pocket demonstrated that regioselectivity of the hydroxylation reactions is determined both by proximity of hydrogens to the iron-oxo complex and by the stability of the carbon radicals generated after hydrogen abstraction. The model explains the activities of all known naturally occurring and synthetic human P450c17 mutants. The model predicted that mutation of lysine 89 would disrupt 17,20-lyase activity to a greater extent than 17alpha-hydroxylase activity; expression of a test mutant, K89N, in yeast confirmed this prediction. Hydrogen peroxide did not support catalysis of the 17,20-lyase reaction, as would be predicted by mechanisms involving a ferryl peroxide. Our present model and biochemical data suggest that both the hydroxylase and lyase activities proceed from a common steroid-binding geometry by an iron oxene mechanism. This model will facilitate studies of sex steroid synthesis and its disorders and the design of specific inhibitors useful in chemotherapy of sex steroid-dependent cancers.

Amino Acid Sequence↗