Harmonic modes as variables to approximately account for receptor flexibility in ligand–receptor docking simulations: Application to DNA minor groove ligand complex

An approach to approximately account for receptor flexibility in ligand–receptor docking simulations is described and applied to a DNA/Hoechst 33258 analogue complex. Harmonic modes corresponding to eigenvectors with small eigenvalues of the Hessian matrix of the potential energy function were used as independent variables to describe receptor flexibility. For the DNA minor groove ligand case most of the conformational difference between an energy minimized free DNA and ligand-bound structure could be assigned to 5–40 harmonic receptor modes with small eigenvalues. During docking, deformations of the DNA receptor structure in the subset of harmonic modes were limited using a simple penalty function that avoided the summation over all intrareceptor atom pairs. Significant improvement of the sterical fit between ligand and receptor was found upon relaxation of the DNA in the subset of harmonic modes after docking of the ligand at the position found in the known crystal structure. In addition, the harmonic mode relaxation resulted in DNA structures that were more similar to the energy minimized ligand-bound form. Although harmonic mode relaxation also leads to improved sterical fit for other ligand placements, the placement as observed in the crystal structure could still be identified as the site with the most favorable sterical interactions. Because relaxation in the harmonic modes is orders of magnitude faster than conventional energy minimization using all atom coordinates as independent variables, the approach might be useful as a preselection tool to recognize ligand binding sites accessible only upon small conformational changes of the receptor. The harmonic mode relaxed structures can only be considered as approximate structures because deformation of the receptor in the harmonic modes can lead to small perturbations of the stereochemical geometry of the molecule. Energy minimization of preselected ligand–DNA docking candidates in all atom coordinates is required to reduce these deviations. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 287–300, 1999     

A new Lamarckian genetic algorithm for flexible ligand‐receptor docking

We present a Lamarckian genetic algorithm (LGA) variant for flexible ligand‐receptor docking which allows to handle a large number of degrees of freedom. Our hybrid method combines a multi‐deme LGA with a recently published gradient‐based method for local optimization of molecular complexes. We compared the performance of our new hybrid method to two non gradient‐based search heuristics on the Astex diverse set for flexible ligand‐receptor docking. Our results show that the novel approach is clearly superior to other LGAs employing a stochastic optimization method. The new algorithm features a shorter run time and gives substantially better results, especially with increasing complexity of the ligands. Thus, it may be used to dock ligands with many rotatable bonds with high efficiency. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Flexible protein‐ligand docking using the Fleksy protocol

Considering protein plasticity is important in accurately predicting the three‐dimensional geometry of protein‐ligand complexes. Here, we present the first public release of our flexible docking tool Fleksy, which is able to consider both ligand and protein flexibility in the docking process. We describe the workflow and different features of the software and present its performance on two cross‐docking benchmark datasets. © 2012 Wiley Periodicals, Inc.     

Flexible ligand docking using a genetic algorithm

Summary Two computational techniques have been developed to explore the orientational and conformational space of a flexible ligand within an enzyme. Both methods use the Genetic Algorithm (GA) to generate conformationally flexible ligands in conjunction with algorithms from the DOCK suite of programs to characterize the receptor site. The methods are applied to three enzyme-ligand complexes: dihydrofolate reductase-methotrexate, thymidylate synthase-phenolpthalein and HIV protease-thioketal haloperidol. Conformations and orientations close to the crystallographically determined structures are obtained, as well as alternative structures with low energy. The potential for the GA method to screen a database of compounds is also examined. A collection of ligands is evaluated simultaneously, rather than docking the ligands individually into the enzyme.Abbreviations GA genetic algorithm; dhfr, dihydrofolate reductase - mtx methotrexate - ts thymidylate synthase - fen phenolphalein - HIV human immune deficiency virus - hivp HIV protease - thk thioketal haloperidol     

Flexible ligand docking using a robust evolutionary algorithm

A flexible ligand docking protocol based on evolutionary algorithms is investigated. The proposed approach incorporates family competition and adaptive rules to integrate decreasing‐based mutations and self‐adaptive mutations to act as global and local search strategies, respectively. The method is applied to a dihydrofolate reductase enzyme with the anticancer drug methotrexate and two analogues of antibacterial drug trimethoprim. Conformations and orientations closed to the crystallographically determined structures are obtained, as well as alternative structures with low energy. Numerical results indicate that the new approach is very robust. The docked lowest‐energy structures have root‐mean‐square derivations ranging from 0.67 to 1.96 Å with respect to the corresponding crystal structures. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 988–998, 2000     

Evaluation of the performance of four molecular docking programs on a diverse set of protein‐ligand complexes

Many molecular docking programs are available nowadays, and thus it is of great practical value to evaluate and compare their performance. We have conducted an extensive evaluation of four popular commercial molecular docking programs, including Glide, GOLD, LigandFit, and Surflex. Our test set consists of 195 protein‐ligand complexes with high‐resolution crystal structures (resolution ≤2.5 Å) and reliable binding data [dissociation constant (K_d) or inhibition constant (K_i)], which are selected from the PDBbind database with an emphasis on diversity. The top‐ranked solutions produced by these programs are compared to the native ligand binding poses observed in crystal structures. Glide and GOLD demonstrate better accuracy than the other two on the entire test set. Their results are also less sensitive to the starting structures for docking. Comparison of the results produced by these programs at three different computation levels reveal that their accuracy are not always proportional to CPU cost as one may expect. The binding scores of the top‐ranked solutions produced by these programs are in low to moderate correlations with experimentally measured binding data. Further analyses on the outcomes of these programs on three suites of subsets of protein‐ligand complexes indicate that these programs are less capable to handle really flexible ligands and relatively flat binding sites, and they have different preferences to hydrophilic/hydrophobic binding sites. Our evaluation can help other researchers to make reasonable choices among available molecular docking programs. It is also valuable for program developers to improve their methods further. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Predicting the accuracy of protein–ligand docking on homology models

Ligand–protein docking is increasingly used in Drug Discovery. The initial limitations imposed by a reduced availability of target protein structures have been overcome by the use of theoretical models, especially those derived by homology modeling techniques. While this greatly extended the use of docking simulations, it also introduced the need for general and robust criteria to estimate the reliability of docking results given the model quality. To this end, a large‐scale experiment was performed on a diverse set including experimental structures and homology models for a group of representative ligand–protein complexes. A wide spectrum of model quality was sampled using templates at different evolutionary distances and different strategies for target–template alignment and modeling. The obtained models were scored by a selection of the most used model quality indices. The binding geometries were generated using AutoDock, one of the most common docking programs. An important result of this study is that indeed quantitative and robust correlations exist between the accuracy of docking results and the model quality, especially in the binding site. Moreover, state‐of‐the‐art indices for model quality assessment are already an effective tool for an a priori prediction of the accuracy of docking experiments in the context of groups of proteins with conserved structural characteristics. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Modelling of ligand–receptor interactions: ab-initio and DFT calculations of solvent reaction field effects on methylated ammonium–π and –acetate complexes

Interaction energies of increasingly methylated ammonium ions with aromatics (benzene, phenol, indole) and with acetate were calculated in vacuo and under the influence of polar media in order to model the binding of ammonium group containing ligands to receptors that offer either carboxylic or aromatic amino acid side chains as ligand anchoring alternatives. Semiempirical, ab-initio and DFT methods were applied to in vacuo calculations while the latter was used at the B3LYP6-31G(d) level in connection with the SCRF procedure of Miertu et al. [Chem. Phys. 55 (1981) 117] to simulate the free energies of transfer from the aqueous (=78.3) to the proteinaceous medium (=20). The in vacuo absolute interaction energies decrease with increasing methylation but the opposite becomes true under the influence of SCRF; only in the example of the tetramethylammonium ion the free energy stays negative. Concerning the interaction of the latter with acetate, it is only slightly more favourable than the binding of tetramethylammonium to indole. This result indicates that aromatic side chains are thermodynamically comparable to the carboxylic ones in the recognition process of the respective receptors for acetylcholine type ligands.     

A molecular mechanics/grid method for evaluation of ligand–receptor interactions

We present a computational method for prediction of the conformation of a ligand when bound to a macromolecular receptor. The method is intended for use in systems in which the approximate location of the binding site is known and no large-scale rearrangements of the receptor are expected upon formation of the complex. The ligand is initially placed in the vicinity of the binding site and the atomic motions of the ligand and binding site are explicitly simulated, with solvent represented by an implicit solvation model and using a grid representation for the bulk of the receptor protein. These two approximations make the method computationally efficient and yet maintain accuracy close to that of an all-atom calculation. For the benzamidine/trypsin system, we ran 100 independent simulations, in many of which the ligand settled into the low-energy conformation observed in the crystal structure of the complex. The energy of these conformations was lower than and well-separated from that of others sampled. Extensions of this method are also discussed. © 1995 by John Wiley & Sons, Inc.     

VoteDock: Consensus docking method for prediction of protein–ligand interactions

Molecular recognition plays a fundamental role in all biological processes, and that is why great efforts have been made to understand and predict protein–ligand interactions. Finding a molecule that can potentially bind to a target protein is particularly essential in drug discovery and still remains an expensive and time‐consuming task. In silico, tools are frequently used to screen molecular libraries to identify new lead compounds, and if protein structure is known, various protein–ligand docking programs can be used. The aim of docking procedure is to predict correct poses of ligand in the binding site of the protein as well as to score them according to the strength of interaction in a reasonable time frame. The purpose of our studies was to present the novel consensus approach to predict both protein–ligand complex structure and its corresponding binding affinity. Our method used as the input the results from seven docking programs (Surflex, LigandFit, Glide, GOLD, FlexX, eHiTS, and AutoDock) that are widely used for docking of ligands. We evaluated it on the extensive benchmark dataset of 1300 protein–ligands pairs from refined PDBbind database for which the structural and affinity data was available. We compared independently its ability of proper scoring and posing to the previously proposed methods. In most cases, our method is able to dock properly approximately 20% of pairs more than docking methods on average, and over 10% of pairs more than the best single program. The RMSD value of the predicted complex conformation versus its native one is reduced by a factor of 0.5 Å. Finally, we were able to increase the Pearson correlation of the predicted binding affinity in comparison with the experimental value up to 0.5. © 2010 Wiley Periodicals, Inc. J Comput Chem 32: 568–581, 2011     

Assessing protein–ligand docking for the binding of organometallic compounds to proteins

Organometallic compounds are increasingly used as molecular scaffolds in drug development projects; their structural and electronic properties offering novel opportunities in protein–ligand complementarities. Interestingly, while protein–ligand dockings have long become a spearhead in computer assisted drug design, no benchmarking nor optimization have been done for their use with organometallic compounds. Pursuing our efforts to model metal mediated recognition processes, we herein present a systematic study of the capabilities of the program GOLD to predict the interactions of protein with organometallic compounds. The study focuses on inert systems for which no alteration of the first coordination sphere of the metal occurs upon binding. Several scaffolds are used as test systems with different docking schemes and scoring functions. We conclude that ChemScore is the most robust scoring function with ASP and ChemPLP providing with good results too and GoldScore slightly underperforming. This study shows that current state‐of‐the‐art protein‐ligand docking techniques are reliable for the docking of inert organometallic compounds binding to protein. © 2013 Wiley Periodicals, Inc.     

GalaxyDock2: Protein–ligand docking using beta‐complex and global optimization

In this article, an enhanced version of GalaxyDock protein–ligand docking program is introduced. GalaxyDock performs conformational space annealing (CSA) global optimization to find the optimal binding pose of a ligand both in the rigid‐receptor mode and the flexible‐receptor mode. Binding pose prediction has been improved compared to the earlier version by the efficient generation of high‐quality initial conformations for CSA using a predocking method based on a beta‐complex derived from the Voronoi diagram of receptor atoms. Binding affinity prediction has also been enhanced by using the optimal combination of energy components, while taking into consideration the energy of the unbound ligand state. The new version has been tested in terms of binding mode prediction, binding affinity prediction, and virtual screening on several benchmark sets, showing improved performance over the previous version and AutoDock, on which the GalaxyDock energy function is based. GalaxyDock2 also performs better than or comparable to other state‐of‐the‐art docking programs. GalaxyDock2 is freely available at http://galaxy.seoklab.org/softwares/galaxydock.html . © 2013 Wiley Periodicals, Inc.     

Semiempirical calculations of binding enthalpy for protein–ligand complexes

A systematic semiempirical quantum mechanical study of the interactions between proteins and ligands has been performed to determine the ability of this approach for the accurate estimation of the enthalpic contribution to the binding free energy of the protein–ligand systems. This approach has been applied for eight test protein–ligand complexes with experimentally known binding enthalpies. The calculations were performed using the semiempirical PM3 approach incorporated in the MOPAC 97, ZAVA originally elaborated in Algodign, and MOPAC 2002 with MOZYME facility packages. Special attention was paid to take into account structural water molecules, which were located in the protein–ligand binding site. It was shown that the results of binding enthalpy calculations fit experimental data within ～2 kcal/mol in the presented approach. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2004     

Reaction of ruthenium complexes containing heterocyclic thiazine–thione ligand

Treatment of the ruthenium complex [Ru]---

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(3, [Ru]=Cp(dppe)Ru) containing a heterocyclic [1,3]-thiazine-4-thione six-membered-ring ligand with various organic halides results in alkylation at the thione sulfur terminus of the ligand to yield [Ru]---

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][X] (4a, R=CN, X=I; 4b, R=Ph, X=Br; 4c, R=CH=CH₂, X=I, 4d, R=p-C₆H₄CF₃, X=Br). Similarly the reaction of 3 with HgCl₂ at room temperature affords [Ru]---

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][Cl] (5). Transformation of 5 to the cationic vinylidene complex {[Ru]=C=C(Ph)C(O)NHPh}₂[Hg₂Cl₆] (6) readily occurred in the air. The structures of 4c and 6 are determined by single crystal X-ray diffraction analysis.     

Representing receptor flexibility in ligand docking through relevant normal modes

Inspired by the current representation of the ligand-receptor binding process, a normal-mode-based methodology is presented to incorporate receptor flexibility in ligand docking and virtual screening. However, the systematic representation of the deformation space grows geometrically with the number of modes, and furthermore, midscale loop rearrangements like those found in protein kinase binding pockets cannot be accounted for with the first lowest-frequency modes. We thus introduced a measure of relevance of normal modes on a given region of interest and showed that only very few modes in the low-frequency range are necessary and sufficient to describe loop flexibility in cAMP-dependent protein kinase. We used this approach to generate an ensemble of representative receptor backbone conformations by perturbing the structure along a combination of relevant modes. Each ensemble conformation is complexed with known non-native binders to optimize the position of the binding-pocket side chains through a full flexible docking procedure. The multiple receptor conformations thus obtained are used in a small-scale virtual screening using receptor ensemble docking. We evaluated this algorithm on holo and apo structures of cAMP-dependent protein kinase that exhibit backbone rearrangements on two independent loop regions close to the binding pocket. Docking accuracy is improved, since the ligands considered in the virtual screening docked within 1.5 A to at least one of the structures. The discrimination between binders and nonbinders is also enhanced, as shown by the improvement of the enrichment factor. This constitutes a new step toward the systematic integration of flexible ligand-flexible receptor docking tools in structure-based drug discovery.     

A large decoy set of protein–protein complexes produced by flexible docking

Computational methods are needed to help characterize the structure and function of protein–protein complexes. To develop and improve such methods, standard test problems are essential. One important test is to identify experimental structures from among large sets of decoys. Here, a flexible docking procedure was used to produce such a large ensemble of decoy complexes. In addition to their use for structure prediction, they can serve as a proxy for the nonspecific, protein–protein complexes that occur transiently in the cell, which are hard to characterize experimentally, yet biochemically important. For 202 homodimers and 41 heterodimers with known X‐ray structures, we produced an average of 1217 decoys each. The structures were characterized in detail. The decoys have rather large protein–protein interfaces, with at least 45 residue–residue contacts for every 100 contacts found in the experimental complex. They have limited intramonomer deformation and limited intermonomer steric conflicts. The decoys thoroughly sample each monomer's surface, with all the surface amino acids being part of at least one decoy interface. The decoys with the lowest intramonomer deformation were analyzed separately, as proxies for nonspecific protein–protein complexes. Their interfaces are less hydrophobic than the experimental ones, with an amino acid composition similar to the overall surface composition. They have a poorer shape complementarity and a weaker association energy, but are no more fragmented than the experimental interfaces, with 2.1 distinct patches of interacting residues on average, compared to 2.6 for the experimental interfaces. The decoys should be useful for testing and parameterizing docking methods and scoring functions; they are freely available as PDB files at http://biology.polytechnique.fr/decoys . © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Thermoregulated ligand–palladium‐catalyzed Suzuki reaction in water

An efficient and recyclable protocol for the Suzuki reaction in water has been developed based on the cloud point of thermoregulated ligand Ph₂P(CH₂CH₂O)_nCH₃ (n = 22). This method allows the preparation of a variety of biaryls in high yields and the catalytic system can be recycled four times with high efficiency. Copyright © 2010 John Wiley & Sons, Ltd.     

Fluorescence properties of polyacrylic acid derivative–Eu3+ ion–low molecular ligand complexes

The polyacrylic acid derivative, the copolymer (PABAM) of acrylic acid (AA) and p-benzoic acid acrylamide (BAM) were prepared by polymeric reaction. The coordinate structure of the polymer–Eu³⁺ complexes was characterized by X-ray photoelectron spectroscopy. The fluorescence intensity of the PABAM–Eu³⁺ complex was enhanced because of introduction of a BAM unit in the polyacrylic acid and reached a maximum when the mole ratio of AA to BAM was about 1 : 1. The ternary complexes of Eu³⁺–polymer–1,10-phenanthroline (PRL), or 2,2-bipyridine (BPD) were synthesized. The polymers used were PABAM and polyacrylic acid (PAA). The fluorescence intensity of the polymer–Eu³⁺ complexes was increased by 5∼21 times owing to the introduction of PRL and BPD.     

Interaction energy‐based drug–receptor interaction study of metal–bicyclam complexes

Bicyclams inhibit HIV replication by binding to the CXCR4 chemokine receptor, which is the main coreceptor for gp120 used by X4, T‐tropic strains of HIV for membrane fusion and cell entry. Bicyclam AMD3100 mainly interacts with the aspartic acid residues namely Asp171 and Asp262, which are located at the extracellular ends in the CXCR4 coreceptor. Incorporation of some metal ions by the macrocyclic rings of bicyclam enhances its binding affinity to the CXCR4 receptor and enhances their anti‐HIV activity because the acetate can make a strong coordination bond to the metal and one weaker hydrogen bond to nitrogen in the cyclam ring. The interaction energy (E_int) between 150 metal–bicyclam complexes and aspartic acid has been evaluated. The metal–bicyclam complexes are obtained by the incorporation of six metal ions namely Fe³⁺, Co³⁺, Ni²⁺, Cu²⁺, Zn²⁺, and Pd²⁺ in 25 well‐known bicyclams including AMD3100. In most of the cases, Fe and Co–bicyclam complexes interact best with aspartic acid. The anti‐HIV activity of metal–bicyclam complexes can be predicted on the basis of interaction energy before the synthesis of the metal–bicyclam complex. On the basis of interaction energy, the anti‐HIV activity of bicyclam complexes can be predicted in advance to their synthesis. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011