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Results for “Molecular Docking Simulation”

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PubMed2006

The structure of the endoribonuclease XendoU: From small nucleolar RNA processing to severe acute respiratory syndrome coronavirus replication.

Small nucleolar RNAs (snoRNAs) play a key role in eukaryotic ribosome biogenesis. In most cases, snoRNAs are encoded in introns and are released through the splicing reaction. Some snoRNAs are, instead, produced by an alternative pathway consisting of endonucleolytic processing of pre-mRNA. XendoU, the endoribonuclease responsible for this activity, is a U-specific, metal-dependent enzyme that releases products with 2'-3' cyclic phosphate termini. XendoU is broadly conserved among eukaryotes, and it is a genetic marker of nidoviruses, including the severe acute respiratory syndrome coronavirus, where it is essential for replication and transcription. We have determined by crystallography the structure of XendoU that, by refined search methodologies, appears to display a unique fold. Based on sequence conservation, mutagenesis, and docking simulations, we have identified the active site. The conserved structural determinants of this site may provide a framework for attempting to design antiviral drugs to interfere with the infectious nidovirus life cycle.

Amino Acid Sequence↗

PubMed2006

Structural model of the BCL-w-BID peptide complex and its interactions with phospholipid micelles.

A peptide corresponding to the BH3 region of the proapoptotic protein, BID, could be bound in the cleft of the antiapoptotic protein, BCL-w. This binding induced major conformational rearrangements in both the peptide and protein components of the complex and led to the displacement and unfolding of the BCL-w C-terminal alpha-helix. The structure of BCL-w with a bound BID-BH3 peptide was determined using NMR spectroscopy and molecular docking. These studies confirmed that a region of 16 residues of the BID-BH3 peptide is responsible for its strong binding to BCL-w and BCL-x(L). The interactions of BCL-w and the BID-BH3 peptide complex with dodecylphosphocholine micelles were characterized and showed that the conformational change of BCL-w upon lipid binding occurred at the same time as the release and unfolding of the BH3 peptide.

Animals↗

PubMed2006

Designing better drugs: predicting cytochrome P450 metabolism.

Many 3D ligand-based and structure-based computational approaches have been used to predict, and thus help explain, the metabolism catalyzed by the enzymes of the cytochrome P450 superfamily (P450s). P450s are responsible for >90% of the metabolism of all drugs, so the computational prediction of metabolism can help to design out drug-drug interactions in the early phases of the drug discovery process. Computational methodologies have focused on a few P450s that are directly involved in drug metabolism. The recently derived crystal structures for human P450s enable better 3D modelling of these important metabolizing enzymes. Models derived for P450s have evolved from simple comparisons of known substrates to more-elaborate experiments that require considerable computer power involving 3D overlaps and docking experiments. These models help to explain and, more importantly, predict the involvement of P450s in the metabolism of specific compounds and guide the drug-design process.

Binding Sites↗

PubMed2003

Molecular recognition and docking algorithms.

Molecular docking is an invaluable tool in modern drug discovery. This review focuses on methodological developments relevant to the field of molecular docking. The forces important in molecular recognition are reviewed and followed by a discussion of how different scoring functions account for these forces. More recent applications of computational chemistry tools involve library design and database screening. Last, we summarize several critical methodological issues that must be addressed in future developments.

Algorithms↗

PubMedDate not supplied

Molecular dynamics simulations of the ligand-induced chemical information transfer in the 5-HT(1A) receptor.

Comparative molecular dynamics simulations of the 5-HT(1A) receptor in its empty as well as agonist- (i.e. active) and antagonist-bound (i.e. nonactive) forms have been carried out. The agonists 5-HT and (R)-8-OH-DPAT as well as the antagonist WAY100635 have been employed. The results of this study strengthen the hypothesis that the receptor portions close to the E/DRY/W motif, with prominence to the cytosolic extensions of helices 3 and 6, are particularly susceptible to undergo structural modification in response to agonist binding. Despite the differences in the structural/dynamics behavior of the two agonists when docked into the 5-HT(1A) receptor, they both exert a destabilization of the intrahelical and interhelical interactions found in the empty and antagonist-bound receptor forms between the arginine of the E/DRY sequence and both D133(3.49) and E340(6.30). For both agonists, the chemical information transfer from the extracellular to the cytosolic domains is mediated by a cluster of aromatic amino acids in helix 6, following the ligand interaction with selected amino acids in the extracellular half of the receptor, such as D116(3.32), S199(5.42), Y195(5.38), and F361(6.51). A significant reduction in the bend at P360(6.50), as compared to the empty and the antagonist-bound receptor forms, is one of the features of the agonist-bound forms that is related to the breakage of the interhelical salt bridge between the E/DRY arginine and E340(6.30). Another structural feature, shared by the agonist-bound receptor forms and not by the empty and antagonist-bound forms, is the detachment of helices 2 and 4, as marked by the movement of W161(4.50) away from helix 2, toward the membrane space.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1995

Ligand-protein docking and rational drug design.

Over the past year there have been some interesting and significant advances in computer-based ligand-protein docking techniques and related rational drug-design tools, including flexible ligand docking and better estimation of binding free energies and solvation energies. As a result, the successful use of computational tools to help generate interesting new guide (lead) compounds for targeted receptors is becoming more commonplace.

Algorithms↗

PubMed2006

A new structural theme in C2-symmetric HIV-1 protease inhibitors: ortho-substituted P1/P1' side chains.

In this report, the rapid syntheses of 24 novel C2-symmetric HIV-1 protease inhibitors are described. Two ortho-iodobenzyloxy containing C-terminal duplicated inhibitors served as starting materials for microwave-enhanced palladium(0)-catalyzed carbon-carbon bond forming reactions (Suzuki, Sonogashira, Heck, and Negishi). Highly potent inhibitors equipped with ortho-functionalized P1/P1' side chains as the structural theme were identified. Computational efforts were applied to study the binding mode of this class of inhibitors and to establish structure-activity relationships. The overall orientation of the inhibitors in the active site was reproduced by docking which suggested three possible conformations of the P1/P1' groups of which two seem more plausible.

Amides↗

PubMed2003

Computer modeling of selective regions in the active site of nitric oxide synthases: implication for the design of isoform-selective inhibitors.

Selective inhibition of nitric oxide synthase (NOS) isoforms has great therapeutic potential in the treatment of certain disease states arising from the pathological overproduction of nitric oxide. In this study three structures of each NOS isoform were employed to examine selective regions in the active site using the GRID/CPCA approach. In the GRID calculations, 10 probes covering hydrophobic, steric, and hydrogen-bond-acceptor and -donor interactions were used to calculate the molecular interaction fields (MIFs) in the active site. The side chain flexibility of the residues and the grid spacings were considered at the same time. Consensus principal component analysis (CPCA) was applied to analyze the MIFs differences in the active site between the NOS isoforms. By combining the cutout tool with GRID/CPCA pseudofield differential plots, several selective regions in the active site were identified. The selectivity analysis showed that the most important determinants for NOS inhibitor selectivity are hydrophobic and charge-charge interactions. Twenty-five inhibitors of NOS were then docked into the active site using the program AutoDock3.0. The regions identified as being important for selectivity by this method are in excellent agreement with inhibitor structure-activity relationships. A rational usage of the selective region described in this work should make it possible to develop NOS isoform-selective inhibitors.

Binding Sites↗

PubMed2005

Free-energy barriers in MbCO rebinding.

The rebinding of CO to myoglobin (Mb) from locations around the active site is studied using a combination of molecular dynamics and stochastic simulations for native and L29F mutant Mb. The interaction between the dissociated ligand and the protein environment is described by the recently developed fluctuating three-point charge model for the CO molecule. Umbrella sampling along trajectories, previously found to sample the binding site (B) and the Xe4 pocket, is used to construct free-energy profiles for the ligand escape. On the basis of the Smoluchowski equation, the relaxation of different initial population distributions is followed in space and time. For native Mb at room temperature, the calculated rebinding times are in good agreement with experimental values and give an inner barrier of 4.3 kcal/mol between the docking site B (Mb...CO) and the A state (bound MbCO), compared to an effective barrier, Heff, of 4.5 kcal/mol and barriers into the majority conformation A1 and the minority conformation A3 of 2.4 and 4.3 kcal/mol, respectively. In the case of the L29F mutant, the free-energy surface is flatter and the dynamics is much more rapid. As was found in experiment, escape to the Xe4 pocket is facile for L29F whereas, for native Mb, the barriers to this site are larger. At lower temperatures, the rebinding dynamics is delayed by orders of magnitude also due to increased barriers between the docking sites.

Binding Sites↗

PubMed2002

Q-fit: a probabilistic method for docking molecular fragments by sampling low energy conformational space.

A new method is presented that docks molecular fragments to a rigid protein receptor. It uses a probabilistic procedure based on statistical thermodynamic principles to place ligand atom triplets at the lowest energy sites. The probabilistic method ranks receptor binding modes so that the lowest energy ones are sampled first. This allows constraints to be introduced to limit the depth of the search leading to a computationally efficient method of sampling low energy conformational space. This is combined with energy minimization of the initial fragment placement to arrive at a low energy conformation for the molecular fragment. Two different search methods are tested involving (i) geometric hashing and (ii) pose clustering methods. Ten molecular fragments were docked that have commonly been used to test docking methods. The success rate was 8/10 and 10/10 for generating a close solution ranked first using the two different sampling procedures. In general, all five of the top ranked solutions reproduce the observed binding mode, which increases confidence in the predictions. A set of ten molecular fragments that have previously been identified as problematic were docked. Success was achieved in 3/10 and 4/10 using the two different methods. Again there is a high level of agreement between the two methods and again in the successful cases the top ranked solutions are correct whilst in the case of the failures none are. The geometric hashing and pose clustering methods are fast averaging approximately 13 and approximately 11 s per placement respectively using conservative parameters. The results are very encouraging and will facilitate the process of finding novel small molecule lead compounds by virtual screening of chemical databases.

Algorithms↗

PubMed1999

Synthesis, computer modeling and biological evaluation of novel protein kinase C agonists based on a 7-membered lactam moiety.

4-Hydroxymethyl-5a-methyl-1,3,4,5,5a beta,6,7,8,9,9a alpha-decahydro-2H-benz[d]azepin-2-ones (4-12), which were designed to mimic the biologically active conformation of teleocidins and benzolactams, were synthesized and evaluated for the ability to compete with [3H]phorbol 12,13-dibutyrate in a PKC delta binding assay. Among the compounds, 10-12 showed potent binding affinity, with inhibition constants (Ki) of low nanomolar order. Computational docking simulation also indicates that the relative positions of the hydrogen-bonding sites and hydrophobic regions of the compounds are well matched to the PKC delta binding site.

Benzazepines↗

PubMed1999

Stereoisomeric selectivity of human deoxyribonucleoside kinases.

Deoxynucleoside kinases catalyze the 5'-phosphorylation of 2'-deoxyribonucleosides with nucleoside triphosphates as phosphate donors. One of the cellular kinases, deoxycytidine kinase (dCK), has been shown to phosphorylate several L-nucleosides that are efficient antiviral agents. In this study we investigated the potentials of stereoisomers of the natural deoxyribonucleoside to serve as substrates for the recombinant cellular deoxynucleoside kinases. The cytosolic thymidine kinase exhibited a strict selectivity and phosphorylated only beta-D-Thd, while the mitochondrial thymidine kinase (TK2) and deoxyguanosine kinase (dGK) as well as dCK all had broad substrate specificities. TK2 phosphorylated Thd and dCyd stereoisomers in the order: beta-D- > or = beta-L- >> alpha-D- > or = alpha-L-isomer. dCK activated both enantiomers of beta-dCyd, beta-dGuo, and beta-dAdo with similar efficiencies, and alpha-D-dCyd also served as a substrate. dGK phosphorylated the beta-dGuo enantiomers with no preference for the ribose configuration; alpha-L-dGuo was also phosphorylated, and beta-L-dAdo and beta-L-dCyd were substrates but showed reduced efficiencies. The anomers of the 2',3'-dideoxy-D-nucleosides (ddNs) were tested, and TK2 and dCK retained their low selectivities. Unexpectedly, alpha-dideoxycytidine (ddC) was a 3-fold better substrate for dCK than beta-ddC. Similarly, alpha-dideoxythymidine (ddT) was a better substrate for TK2 than beta-ddT. dGK did not accept any D-ddNs. Thus, TK2, dCK, and dGK, similar to herpes simplex virus type 1 thymidine kinase (HSV-1 TK), showed relaxed stereoselectivities, and these results substantiate the functional similarities within this enzyme family. Docking simulations with the Thd isomers and the active site of HSV-1 TK showed that the viral enzyme may in some respects serve as a model for studying the substrate specificities of the cellular enzymes.

Binding Sites↗

PubMed2005

Spirohydantoin derivatives of thiopyrano[2,3-b]pyridin-4(4H)-one as potent in vitro and in vivo aldose reductase inhibitors.

The 2,3-dihydrospiro[4H-thiopyrano[2,3-b]pyridin-4,4'-imidazolidine]-2',5'-dione 3 and its 7-methyl analogue 4 were synthesized and tested for their ability to inhibit aldose reductase (ALR2). To expand the structure-activity relationships, the sulfone 5 and the acetic acid derivative 7 were also prepared and tested. Compounds 3 and 4 proved to be potent ALR2 inhibitors, with IC50 values in the submicromolar range (0.96 and 0.94 microM, respectively) similar to that of sorbinil (0.65 microM). Moreover, compound 3 was found to be highly potent in preventing cataract development in severely galactosemic rats, like tolrestat, when administered as an eyedrop solution. Docking simulations of both R- and S-isomers of 3 into the ALR2 crystal structure were carried out to guide, prospectively, the design of new analogues.

Aldehyde Reductase↗

PubMed2003

A computationally derived structural model of doxorubicin interacting with oligomeric polyalkylcyanoacrylate in nanoparticles.

We report a molecular simulation study of doxorubicin interacting within a frame of n-butyl polycyanoacrylate, one of the most commonly encountered polymers in the production of nanoparticles. Emphasis is put on the tetrameric, hexameric and octameric oligomers (PACA's). Log P was calculated for all interacting species. Molecular dynamics along with energy minimization processes (molecular mechanics MM2, semi-empirical quantum mechanics PM3) were employed to probe the conformational behavior of doxorubicin and polyalkylcyanoacrylate both as isolated species and interacting with each other. A docked structure of protonated doxorubicin with two octamers of n-butyl polycyanoacrylate is described. Among the main stability factors of the assembly was the charge-dipole interaction representing a stabilizing contribution of -33 kcal/mol. The mechanism of aggregation and desegregation (doxorubicin release) can be summarized as follows: oligomeric PACA's are lipophilic entities that scavenge amphiphilic doxorubicin already during the polymerization process by extraction of the protonated species from the aqueous environment to the increasingly lipophilic phase of the growing PACA's. The establishment of hydrogen bonds between the ammonium N-H function and the cyano groups is noteworthy. The cohesion in PACA nanoparticle comes therefore from a blend of dipole-charge interaction, H bonds, and hydrophobic forces,

Cyanoacrylates↗

PubMed1998

A model for the function of the bisphosphorylated heart-specific troponin-I N-terminus.

Bisphosphorylation of two adjacently located serine residues in the heart-specific N-terminus of the cTnl subunit reduces calcium affinity of the cTnC subunit. An interaction of the phosphorylation region of cTnI with acidic residues of another cTn subunit has been proposed formerly based on 31P nuclear magnetic resonance (NMR) data. A possible candidate is cTnC. Thus, an interaction model of cTnC with the bisphosphorylated cTnI N-terminus has been built using a homology model of hcTnC based on the crystal structure of tusTnC and the structure of the phosphorylation region of cTnI determined by 2D NMR. By computational search, five cluster of acidic residues of cTnC might interact with the cTnI phosphorylation region. Three sites could be excluded by 31P-NMR experiments. The two remaining sites are located in the N-terminal helix of cTnC and between calcium binding sites III and IV. Reorientation of the arginine and phosphoserine sidechains within the phosphorylation region as proposed by refined docking could explain the formerly measured changes in pKaapp values. Thus, local pKa changes might lead to the reduction of calcium affinity observed upon cTnI bisphosphorylation.

Amino Acid Sequence↗

PubMed2002

SOFTDOCK: understanding of molecular recognition through a systematic docking study.

Molecular recognition and docking are essential to the biological functions of proteins. SOFTDOCK was one of the first molecular docking methods developed for protein-protein docking. Its ability to represent the molecular surface with different shapes and properties and to dock a variety of molecular complexes with certain conformational changes was demonstrated in a previous study. In the present work, we studied the effects of the docking parameters through statistical analysis. Seventy one typical binary complexes of different categories in PDB were also systematically docked for a test; 57 of them produced correct solutions with one set of docking parameters whereas the other 14 complexes required adjustment of the docking parameters, by decreasing the softness of the recognition and hence the background noise. We found that these 14 complexes had special structural features. Our results suggest that a variety of mechanisms may be involved in molecular recognition rather than the shape complementarity only, which is very helpful in developing more powerful methods for predicting molecular recognition.

Binding Sites↗

PubMed1997

Molecular modeling of cytochrome P450 3A4.

The three-dimensional structure of human cytochrome P450 3A4 was modeled based on crystallographic coordinates of four bacterial P450s; P450 BM-3, P450cam, P450terp, and P450eryF. The P450 3A4 sequence was aligned to those of the known proteins using a structure-based alignment of P450 BM-3, P450cam, P450terp, and P450eryF. The coordinates of the model were then calculated using a consensus strategy, and the final structure was optimized in the presence of water. The P450 3A4 model resembles P450 BM-3 the most, but the B' helix is similar to that of P450eryF, which leads to an enlarged active site when compared with P450 BM-3, P450cam, and P450terp. The 3A4 residues equivalent to known substrate contact residues of the bacterial proteins and key residues of rat P450 2B1 are located in the active site or the substrate access channel. Docking of progesterone into the P450 3A4 model demonstrated that the substrate bound in a 6 beta-orientation can interact with a number of active site residues, such as 114, 119, 301, 304, 305, 309, 370, 373, and 479, through hydrophobic interactions. The active site of the enzyme can also accommodate erythromycin, which, in addition to the residues listed for progesterone, also contacts residues 101, 104, 105, 214, 215, 217, 218, 374, and 478. The majority of 3A4 residues which interact with progesterone and/or erythromycin possess their equivalents in key residues of P450 2B enzymes, except for residues 297, 480 and 482, which do not contact either substrate in P450 3A4. The results from docking of progesterone and erythromycin into the enzyme model make it possible to pinpoint residues which may be important for 3A4 function and to target them for site-directed mutagenesis.

Amino Acid Sequence↗

PubMed1999

Exhaustive docking of molecular fragments with electrostatic solvation.

A new method is presented for docking molecular fragments to a rigid protein with evaluation of the binding energy. Polar fragments are docked with at least one hydrogen bond with the protein while apolar fragments are positioned in the hydrophobic pockets. The electrostatic contribution to the binding energy, which consists of screened intermolecular energy and protein and fragment desolvation terms, is evaluated efficiently by a numerical approach based on the continuum dielectric approximation. The latter is also used to predetermine the hydrophobic pockets of the protein by rolling a low dielectric sphere over the protein surface and calculating the electrostatic desolvation of the protein and van der Waals interaction energy. The method was implemented in the program SEED (solvation energy for exhaustive docking). The SEED continuum electrostatic approach has been successfully validated by a comparison with finite difference solutions of the Poisson equation for more than 2,500 complexes of small molecules with thrombin and the monomer of HIV-1 aspartic proteinase. The fragments docked by SEED in the active site of thrombin reproduce the structural features of the interaction patterns between known inhibitors and thrombin. Moreover, the combinatorial connection of these fragments yields a number of compounds that are very similar to potent inhibitors of thrombin. Proteins 1999;37:88-105.

Computer Simulation↗