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PubMed2006

Critical assessment of the automated AutoDock as a new docking tool for virtual screening.

A major problem in virtual screening concerns the accuracy of the binding free energy between a target protein and a putative ligand. Here we report an example supporting the outperformance of the AutoDock scoring function in virtual screening in comparison to the other popular docking programs. The original AutoDock program is in itself inefficient to be used in virtual screening because the grids of interaction energy have to be calculated for each putative ligand in chemical database. However, the automation of the AutoDock program with the potential grids defined in common for all putative ligands leads to more than twofold increase in the speed of virtual database screening. The utility of the automated AutoDock in virtual screening is further demonstrated by identifying the actual inhibitors of various target enzymes in chemical databases with accuracy higher than the other docking tools including DOCK and FlexX. These results exemplify the usefulness of the automated AutoDock as a new promising tool in structure-based virtual screening.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1992

A multiple-start Monte Carlo docking method.

We present a method to search for possible binding modes of molecular fragments at a specific site of a potential drug target of known structure. Our method is based on a Monte Carlo (MC) algorithm applied to the translational and rotational degrees of freedom of the probe fragment. Starting from a randomly generated initial configuration, favorable binding modes are generated using a two-step process. An MC run is first performed in which the energy in the Metropolis algorithm is substituted by a score function that measures the average distance of the probe to the target surface. This has the effect of making buried probes move toward the target surface and also allows enhanced sampling of deep pockets. In a second MC run, a pairwise atom potential function is used, and the temperature parameter is slowly lowered during the run (Simulated Annealing). We repeat this procedure starting from a large number of different randomly generated initial configurations in order to find all energetically favorable docking modes in a specified region around the target. We test this method using two inhibitor-receptor systems: Streptomyces griseus proteinase B in complex with the third domain of the ovomucoid inhibitor from turkey, and dihydrofolate reductase from E. coli in complex with methotrexate. The method could consistently reproduce the complex found in the crystal structure searching from random initial positions in cubes ranging from 25 A to 50 A about the binding site. In the case of SGPB, we were also successful in docking to the native structure. In addition, we were successful in docking small probes in a search that included the entire protein surface.

Algorithms↗
PubMed1992

Monte Carlo docking of oligopeptides to proteins.

A new two-step procedure has been developed for the docking of flexible oligopeptide chains of unknown conformation to static proteins of known structure. In the first step positions and conformations are sampled and the association energy minimized starting from an approximate preselected docking position. The resulting conformations are further optimized in the second step by a Metropolis Monte Carlo minimization, which optimizes each of these structures. The method has been tested on the HIV-1 aspartic proteinase complex with an inhibitor, whose crystallographic structure is known at 2.3 A resolution. Furthermore, the application of this method to the docking of the hendecapeptide 58-68 of the influenza A virus matrix protein to the HLA-A2 molecule produced results which are in agreement with experimental observations in identifying side chains critical for T cell recognition and residues responsible of MHC protein binding.

Algorithms↗
PubMed1993

NMR docking of the competitive inhibitor thymidine 3',5'-diphosphate into the X-ray structure of staphylococcal nuclease.

In the X-ray structure of the ternary staphylococcal nuclease-Ca(2+)-3',5'-pdTp complex, the conformation of the bound inhibitor 3',5'-pdTp is distorted by Lys-70* and Lys-71* from an adjacent molecule of the enzyme in the crystal lattice (Loll, P. J. and Lattman, E. E. Proteins 5:183-201, 1989; Serpersu, E. H., Hibler, D. W., Gerlt, J. A., and Mildvan, A. S. Biochemistry 28:1539-1548, 1989). Since this interaction does not occur in solution, the NMR docking procedure has been used to correct this problem. Based on 8 Co(2+)-nucleus distances measured by paramagnetic effects on T1, and 9 measured and 45 lower limit interproton distances determined by 1D and 2D NOE studies of the ternary Ca2+ complex, the conformation of enzyme-bound 3',5'-pdTp is high-anti (chi = 58 +/- 10 degrees) with a C2' endo/O1' endo sugar pucker (delta = 143 +/- 2 degrees), (-) synclinal about the C3'-O3' bond (epsilon = 273 +/- 4 degrees), trans, gauche about the C4'-C5' bond (gamma = 301 +/- 29 degrees) and either (-) or (+) clinal about the C5'-O5' bond (beta = 92 +/- 8 degrees or 274 +/- 3 degrees). The structure of 3',5'-pdTp in the crystalline complex differs due to rotations about the C4'-C5' bond (gamma = 186 +/- 12 degrees, gauche, trans) and the C5'-O5' bond [beta = 136 +/- 10 degrees, (+) anticlinal]. The undistorted conformation of enzyme-bound metal-3',5'-pdTp determined by NMR was docked into the X-ray structure of the enzyme, using 19 intermolecular NOEs from ring proton resonances of Tyr-85, Tyr-113, and Tyr-115 to proton resonances of the inhibitor. van der Waals overlaps were then removed by energy minimization. Subsequent molecular dynamics and energy minimization produced no significant changes, indicating the structure to be in a global rather than in a local minimum. While the metal-coordinated 5'-phosphate of the NMR-docked structure of 3',5'-pdTp overlaps with that in the X-ray structure, and similarly receives bifunctional hydrogen bonds from both Arg-35 and Arg-87, the thymine, deoxyribose, and 3'-phosphate are significantly displaced from their positions in the X-ray structure, with the 3'-phosphate receiving hydrogen bonds from Lys-49 rather than from Lys-84 and Tyr-85. The repositioned thymine ring permits hydrogen bonding to the phenolic hydroxyl of Tyr-115.(ABSTRACT TRUNCATED AT 400 WORDS)

Binding Sites↗
PubMed1993

Mutational tests of the NMR-docked structure of the staphylococcal nuclease-metal-3',5'-pdTp complex.

In the X-ray structure of the staphylococcal nuclease-Ca(2+)-3',5'-pdTp complex, the conformation of the inhibitor 3',5'-pdTp is distorted by Lys-70* and Lys-71* from an adjacent molecule of staphylococcal nuclease (Loll, P.J., Lattman, E.E. Proteins 5:183-201, 1989). In order to correct this crystal packing problem, the solution conformation of enzyme-bound 3',5'-pdTp in the staphylococcal nuclease-metal-pdTp complex determined by NMR methods was docked into the X-ray structure of the enzyme [Weber, D.J., Serpersu, E.H., Gittis, A.G., Lattman, E.E., Mildvan, A.S. (preceding paper)]. In the NMR-docked structure, the 5'-phosphate of 3',5'-pdTp overlaps with that in the X-ray structure. However, the 3'-phosphate accepts a hydrogen bond from Lys-49 (2.89 A) rather than from Lys-84 (8.63 A), and N3 of thymine donates a hydrogen bond to the OH of Tyr-115 (3.16 A) which does not occur in the X-ray structure (5.28 A). These interactions have been tested by binding studies of 3',5'-pdTp, Ca2+, and Mn2+ to the K49A, K84A, and Y115A mutants of staphylococcal nuclease using water proton relaxation rate and EPR methods. Each mutant was fully active and structurally intact, as found by CD and two-dimensional NMR spectroscopy, but bound Ca2+ 9.1- to 9.9-fold more weakly than the wild-type enzyme. While the K84A mutation did not significantly weaken 3',5'-pdTp binding to the enzyme (1.5 +/- 0.7 fold), the K49A mutation weakened 3',5'-pdTp binding to the enzyme by the factor of 4.4 +/- 1.8-fold. Similarly, the Y115A mutation weakened 3',5'-pdTp binding to the enzyme 3.6 +/- 1.6-fold. Comparable weakening effects of these mutations were found on the binding of Ca(2+)-3',5'-pdTp. These results are more readily explained by the NMR-docked structure of staphylococcal nuclease-metal-3',5'-pdTp than by the X-ray structure.

Binding Sites↗
PubMed1994

Molecular dynamics simulation of the docking of substrates to proteins.

A simple method is described to perform docking of substrates to proteins or probes to receptor molecules by a modification of molecular dynamics simulations. The method consists of a separation of the center-of-mass motion of the substrate from its internal and rotational motions, and a separate coupling to different thermal baths for both types of motion of the substrate and for the motion of the receptor. Thus the temperatures and the time constants of coupling to the baths can be arbitrarily varied for these three types of motion, allowing either a frozen or a flexible receptor and allowing control of search rate without disturbance of internal structure. In addition, an extra repulsive term between substrate and protein was applied to smooth the interaction. The method was applied to a model substrate docking onto a model surface, and to the docking of phosphocholine onto immunoglobulin McPC603, in both cases with a frozen receptor. Using translational temperatures of the substrate in the range of 1300-1700 K and room temperature for the internal degrees of freedom of the substrate, an efficient nontrapping exploratory search ("helicopter view") is obtained which visits the correct binding sites. Low energy conformations can then be further investigated by separate search or by dynamic simulated annealing. In both cases the correct minima were identified. The possibility to work with flexible receptors is discussed.

Antibodies↗
PubMed1995

A continuum model for protein-protein interactions: application to the docking problem.

The prediction of protein-protein interactions in solution is a major goal of theoretical structural biology. Here, we implement a continuum description of the thermodynamic processes involved. The model differs considerably from previous models in its use of "molecular surface" area to describe the hydrophobic component to the free energy of conformational change in solution. We have applied this model to a data set of alternative docked conformations of protein-protein complexes which were generated independently of this work. It was found previously that commonly used energy evaluation techniques fail to distinguish between near-native and certain non-native complexes in this data set. Here, we found that an energy function that takes into account (1) total electrostatic free energy, (2) hydrophobic free energy and (3) loss in side-chain conformational energy was able to reliably discriminate between near-native and non-native configurations but only when molecular surface is used as a descriptor of the hydrophobic effect. It is shown that the molecular surface and the more conventional surface descriptor "solvent accessible surface" give very different quantitative measures of hydrophobicity. In terms of the contribution of different energy components to the free energy of complex formation it was found that loss in side-chain conformational entropy is a second order effect. Electrostatic interaction energy (which is commonly used to score docked conformations) was a poor indicator of complementarity when starting from unbound conformations. It was found that electrostatic desolvation energy and the hydrophobic contribution (based on a molecular surface area descriptor) are much less sensitive to local fluctuations in atomic structure than point-to-point interaction energies and thus may be more suited for use as a scoring function when docking unbound conformations, where atomic complementarity is much less apparent. Whilst a combined energy function was able to distinguish near-native from non-native conformations in the six systems studied here, it remains to be determined to what extent more sizeable conformational changes would influence the results.

Algorithms↗
PubMed1994

GREEN: a program package for docking studies in rational drug design.

A program package, GREEN, has been developed that enables docking studies between ligand molecules and a protein molecule. Based on the structure of the protein molecule, the physical and chemical environment of the ligand-binding site is expressed as three-dimensional grid-point data. The grid-point data are used for the real-time evaluation of the protein-ligand interaction energy, as well as for the graphical representation of the binding-site environment. The interactive docking operation is facilitated by various built-in functions, such as energy minimization, energy contribution analysis and logging of the manipulation trajectory. Interactive modeling functions are incorporated for designing new ligand molecules while considering the binding-site environment and the protein-ligand interaction. As an example of the application of GREEN, a docking study is presented on the complex between trypsin and a synthetic trypsin inhibitor. The program package will be useful for rational drug design, based on the 3D structure of the target protein.

Algorithms↗
PubMed1992

A pseudoreceptor docking study of 4,5-alpha-epoxymorphinans with a range of dielectric constants.

Thirteen 4,5-epoxymorphinan mu agonists with established analgesic action were docked into an Asp-Lys-His-Phe pseudoreceptor complex under a range of distance-dependent dielectric conditions. The number of compounds with potential energies of the docked complexes that agreed in rank order with corresponding analgesic potencies was determined for each condition. Two dielectric conditions, n-decane (1.991) and ethanol (24.3), enabled the greatest number of compounds to relate to their pseudoreceptors with each having 9 and 8 successes respectively. Both of these conditions demonstrated unique influences on the types of structures that were successfully docked. For example, the morphine stereoisomer alpha-isomorphine, the geometric isomer B/C trans-morphine, and the 8-position-substituted gamma-isomorphine were successes in the n-decane condition, whereas the ethanol condition produced the substituted codeine derivatives dihydrocodeinone and dihydroxycodeinone. These findings emphasize the importance of dielectric influence when developing force-field modeled quantitative structure-activity relationships for a closely related homologous series.

Amino Acid Sequence↗
PubMed2002

Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells.

A readily releasable pool (RRP) of granules has been proposed to underlie the first phase of insulin secretion. In the present study we combined electron microscopy, insulin secretion measurements and recordings of cell capacitance in an attempt to define this pool ultrastructurally. Mouse pancreatic B-cells contain approximately 9,000 granules, of which 7% are docked below the plasma membrane. The number of docked granules was reduced by 30% (200 granules) during 10 min stimulation with high K+. This stimulus depolarized the cell to -10 mV, elevated cytosolic [Ca2+] ([Ca2+](i)) from a basal concentration of 130 nM to a peak of 1.3 microM and released 0.5 ng insulin/islet, corresponding to 200-300 granules/cell. The Ca2+ transient decayed towards the prestimulatory concentration within approximately 200 s, presumably reflecting Ca2+ channel inactivation. Renewed stimulation with high K+ failed to stimulate insulin secretion when applied in the absence of glucose. The size of the RRP, derived from the insulin measurements, is similar to that estimated from the increase in cell capacitance elicited by photolytic release of caged Ca2+. We propose that the RRP represents a subset of the docked pool of granules and that replenishment of RRP can be accounted for largely by chemical modification of granules already in place or situated close to the plasma membrane.

Animals↗
PubMed2002

Docking and molecular dynamics studies at trypanothione reductase and glutathione reductase active sites.

A theoretical docking study on the active sites of trypanothione reductase (TR) and glutathione reductase (GR) with the corresponding natural substrates, trypanothione disulfide (T[S]2) and glutathione disulfide (GSSG), is reported. Molecular dynamics simulations were carried out in order to check the robustness of the docking results. The energetic results are in agreement with previous experimental findings and show the crossed complexes have lower stabilization energies than the natural ones. To test DOCK3.5, four nitro furanic compounds, previously designed as potentially active anti-chagasic molecules, were docked at the GR and TR active sites with the DOCK3.5 procedure. A good correlation was found between differential inhibitory activity and relative interaction energy (affinity). The results provide a validation test for the use of DOCK3.5 in connection with the design of anti-chagasic drugs.

Binding Sites↗
PubMed2003

Binding mode of ecdysone agonists to the receptor: comparative modeling and docking studies.

Three-dimensional structure models of the ligand-binding domain of the ecdysone receptor of Heliothis virescens were built by the homology modeling technique from the crystal structures of nuclear receptors. Two models were created based both on known ligand-binding domain structures of the receptors with the highest sequence identity to the ecdysone receptor, and on those of steroid hormone receptors. The latter model, which was found to have better stereochemical quality and be in good agreement with the binding of the steroidal framework of the endogenous agonist 20-hydroxyecdysone, was used for docking studies. The docking of 20-hydroxyecdysone to the receptor model revealed that the ligand molecule can interact with the receptor in a similar manner to other steroid hormone-receptor complexes. The docking of a dibenzoylhydrazine agonist, chromafenozide, was performed based on the correspondences between the molecule and 20-dydroxyecdysone expected by molecular comparison. The interactions of the ligands with the receptor in the complexes modeled were investigated and found to be consistent with known structure-activity relationships.

Amino Acid Sequence↗
PubMed2004

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

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

Animals↗
PubMed2005

The 3D structure of the binding pocket of the human oxytocin receptor for benzoxazine antagonists, determined by molecular docking, scoring functions and 3D-QSAR methods.

Molecular docking and 3D-QSAR studies were performed to determine the binding mode for a series of benzoxazine oxytocin antagonists taken from the literature. Structural hypotheses were generated by docking the most active molecule to the rigid receptor by means of AutoDock 3.05. The cluster analysis yielded seven possible binding conformations. These structures were refined by using constrained simulated annealing, and the further ligands were aligned in the refined receptor by molecular docking. A good correlation was found between the estimated deltaG(bind) and the pKi values for complex F. The Connolly-surface analysis, CoMFA and CoMSIA models q2(CoMFA) = 0.653, q2(CoMSA) = 0.630 and r2(pred,CoMFA) = 0.852 , r2(pred,CoMSIA) = 0.815) confirmed the scoring function results. The structural features of the receptor-ligand complex and the CoMFA and CoMSIA fields are in closely connected. These results suggest that receptor-ligand complex F is the most likely binding hypothesis for the studied benzoxazine analogs.

Benzoxazines↗
PubMed2006

Combining NMR relaxation with chemical shift perturbation data to drive protein-protein docking.

The modeling of biomolecular complexes by computational docking using the known structures of their constituents is developing rapidly to become a powerful tool in structural biology. It is especially useful in combination with even limited experimental information describing the interface. Here we demonstrate for the first time the use of diffusion anisotropy in combination with chemical shift perturbation data to drive protein-protein docking. For validation purposes we make use of simulated diffusion anisotropy data. Inclusion of this information, which can be derived from NMR relaxation rates and reports on the orientation of the components of a complex with respect to the rotational diffusion tensor, substantially improves the docking results.

Anisotropy↗
PubMed2026

Structure-based virtual screening, multi-score docking, and molecular dynamics simulation of novel small molecules targeting the epidermal growth factor receptor for potential management of oral squamous cell carcinoma.

UNLABELLED: Oral squamous cell carcinoma (OSCC) is a major global health burden, with epidermal growth factor receptor (EGFR) serving as an important therapeutic target. However, resistance to currently available EGFR inhibitors limits the efficacy of long-term treatment. In this study, a structure-based virtual screening approach was employed using the Mcule database to identify novel small molecules with potential EGFR-inhibitory activity. The top-ranked compounds were subjected to consensus docking using multiple docking platforms and compared with established EGFR inhibitors. The most promising complexes were further evaluated using 500 ns molecular dynamics simulations to investigate their structural stability, conformational flexibility, and binding persistence. ADMET and pharmacokinetic analyses were performed to assess the drug-like and safety profiles. Five lead compounds (C1-C5) demonstrated significant binding affinities toward EGFR, ranging from - 9.9 to - 9.2 kcal/mol, while satisfying the major drug-likeness criteria. Molecular dynamics simulations suggested that C1 and C4 may form relatively stable EGFR-ligand complexes, as supported by stable RMSD convergence and persistent interactions with key active-site residues throughout the simulation period. Trajectory-based interaction analyses further indicated a sustained binding behavior. ADMET profiling predicted favorable oral bioavailability and low predicted toxicity for most compounds, particularly C3 and C5, although a potential risk of cytochrome P450-mediated drug-drug interactions was observed. Overall, the shortlisted compounds exhibited docking and dynamic stability profiles comparable to those of the reference inhibitor Lapatinib. These findings suggest the potential therapeutic relevance of structurally novel EGFR-targeting scaffolds in OSCC and provide a foundation for future experimental validation through in vitro and in vivo studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00722-4.

ADMET↗
PubMed1996

Empirical free energy as a target function in docking and design: application to HIV-1 protease inhibitors.

Structure-based drug design requires the development of efficient computer programs for exploring the structural compatibility of various flexible ligands with a given receptor. While various algorithms are available for finding docked conformations, selecting a target function that can reliably score the conformations remains a serious problem. We show that the use of an empirical free energy evaluation method, originally developed to characterize protein-protein interactions, can substantially improve the efficacy of search algorithms. In addition to the molecular mechanics interaction energy, the function takes account of solvation and side chain conformational entropy, while remaining simple enough to replace the incomplete target functions used in many drug docking and design procedures. The free energy function is used here in conjunction with a simple site mapping-fragment assembly algorithm, for docking the MVT-101 non-peptide inhibitor to HIV-1 protease. In particular, we predict the bound structure with an all atom RMSD of 1.21 A, compared to 1.69 A using an energy target function, and also accurately predict the free energy shifts obtained with a series of five trimeric hydroxyethylene isostere analogs.

Algorithms↗
PubMed1991

Protein docking and complementarity.

Predicting the structures of protein-protein complexes is a difficult problem owing to the topographical and thermodynamic complexity of these structures. Past efforts in this area have focussed on fitting the interacting proteins together using rigid body searches, usually with the conformations of the proteins as they occur in crystal structure complexes. Here we present work which uses a rigid body docking method to generate the structures of three known protein complexes, using both the bound and unbound conformations of the interacting molecules. In all cases we can regenerate the geometry of the crystal complexes to high accuracy. We also are able to find geometries that do not resemble the crystal structure but nevertheless are surprisingly reasonable both mechanistically and by some simple physical criteria. In contrast to previous work in this area, we find that simple methods for evaluating the complementarity at the protein-protein interface cannot distinguish between the configurations that resemble the crystal structure complex and those that do not. Methods that could not distinguish between such similar and dissimilar configurations include surface area burial, solvation free energy, packing and mechanism-based filtering. Evaluations of the total interaction energy and the electrostatic interaction energy of the complexes were somewhat better. Of the techniques that we tried, energy minimization distinguished most clearly between the "true" and "false" positives, though even here the energy differences were surprisingly small. We found the lowest total interaction energy from amongst all of the putative complexes generated by docking was always within 5 A root-mean-square of the crystallographic structure. There were, however, several putative complexes that were very dissimilar to the crystallographic structure but had energies that were close to that of the low energy structure. The magnitude of the error in energy calculations has not been established in macromolecular systems, and thus the reliability of the small differences in energy remains to be determined. The ability of this docking method to regenerate the crystallographic configurations of the interacting proteins using their unbound conformations suggests that it will be a useful tool in predicting the structures of unsolved complexes.

Algorithms↗