Precise Docking Research Articles

Towards more effective acetylcholinesterase inhibitors: a comprehensive modelling study based on human acetylcholinesterase protein–drug complex

Alzheimer's disease is a progressive neurodegenerative disorder and as the exact cause of the disease remains unknown, it still has no cure to date. Due to the fact that, until recently, there has been no crystal structure of human AChE in complex with drugs, researchers have had to use mainly Torpedo californica homologues which were later reported to have significantly different binding sites. In this study, an energy-based pharmacophore model that has the advantages of both ligand- and structure-based approaches was generated using hAChE crystal structures in complex with drugs. This model was validated utilizing several commonly used statistical measures such as the enrichment factor, BEDROC, RIE and AUAC. A huge database consisting of around 7 million compounds with approximately 150,000,000 conformations from 8 vendors was used in virtually screening workflow, in which Lipinski’s filter and basic and precise docking algorithms were utilized. A rigorous MM-GBSA binding affinity calculation was also applied to accurately predict relative free energy that produced 361 hits. The selected top ranked 15 compounds were shown to have extra intermolecular interactions with hAChE which is an indication of a more stable complex and high binding affinity. The e-pharmacophore model and overall results obtained might be used for further experimental studies in designing the next generation of hAChE inhibitors.Communicated by Ramaswamy H. Sarma

Assessment of Astronauts’ Workload with Task-Irrelevant Auditory Probes In Manually Controlled Spacecraft Rendezvous and Docking

Introduction. The rendezvous and docking (RVD) operation is a challenging task of high risk for astronauts. It is an essential part of missions involving more than one spacecraft such as transportation missions for the International Space Station supply. While intensive automation is an indispensable ingredient of the modern RVD operations, manual docking remains one of the critical skills for an astronaut. Manual RVD is a cognitively demanding task that requires a constant sustained attention. The astronaut has to perform a precise docking by minimizing the linear and rotational speeds of the spacecraft using minimum control actions, thus, minimizing the fuel consumption. The performance in RVD operation can be modulated by the astronauts’ workload. Efficient assessment techniques can be used on the ground both for human factor evaluation of the system design and training purposes, as well as in space for adaptive astronaut-spacecraft interaction. In this study, we evaluate whether task-irrelevant auditory probes can be an effective assessment method of astronauts’ workload. Materials and Methods. The docking operation was simulated using the simulator of the Moscow Aviation Institute, which uses two stereographic projectors and 3D-glasses reproduces the immersive experience of the SOYOUZ module docking to the International Space Station (ISS). An astronaut can operate two levers: left lever controls the translational speed (Vx, Vy, Vz), while the right one controls the rotational speed (Wx, Wy, Wz) of the spacecraft. The numerical values of both speeds are displayed on the screen. The levers can be operated with or without feedback. With the feedback, when a lever is released, the corresponding speed is automatically reduced to 0. Visual guiding cues can also be displayed on the screen: a dotted circle indicating the direction of the speed vector, a cross corresponding to the projection of the docking in the current configuration, and a corridor represented with four trajectory lines perpendicular to the final contact plan of the docking. Three scenarios were used to modulate the participants’ workload. In the first scenario, both levers feedback and visual cues were present. In the second scenario, only feedback was present. In the third one, only visual cues were present. Three participants with docking simulator experience performed three times each docking scenario. The workload was measured using task-irrelevant auditory probes. The participants were presented with 200 ms high (2 kHz) and low (1 kHz) tones in 20/80% proportion with a variable inter-stimuli interval from 2 to 3 seconds. They were asked to verbally report the rare high tones and their response times were measured. The participants evaluated each scenario using NASA-TLX questionnaire dimensions. Results. The participants performed fewer input actions for the scenario n°2 with visual cues only. While most efficient for fuel consumption, the second scenario induced the least accurate final docking positions, and was considered by participants as the most demanding both mentally and physically. The response times were consistent with the subjective and objective difficulty of the scenarios: 475.3 ms on average for the scenario n°2 vs 412.4 ms for the scenario n°1 and 387.6 ms for the scenario n°3. Conclusion. The presented work showed that a simple technique of task-irrelevant auditory probes can be used to assess the astronauts’ workload during manual controlled spacecraft rendezvous and docking. The participants of this experiment in SOYOUZ module simulator showed less accurate docking in a scenario without lever feedback. They also evaluated this scenario as particularly cognitively and physically demanding. The response times to irrelevant high-pitch tones were in line with the objective (performance) and subjective (questionnaire) measurement of the scenarios’ difficulty. Therefore, this simple technique can be used in such situations as manual RVD in order to evaluate the astronauts' workload.

Precise docking technology in full-automatic quick hitch coupling device

Precise docking technology in full-automatic quick hitch coupling device

Key Technologies in Large-scale Rescue Robot Wrists

The full-Automatic Quick Hitch Coupling Device (full-AQHCD for short) is used as the starting point, key technologies in a large-scale rescue robot wrist, which is constituted by integrating a quick hitch coupling device, a turning device, and a swaying device together, are reviewed respectively. Firstly, the semi-AQHCD made domestically for the main-Arm Claw Wrist (main-ACW for short) is introduced, and the full-AQHCD imported from Oil Quick company in Sweden for the vice-Arm Cutter Wrist (vice-ACW for short) is presented. Secondly, aiming at three key technologies in the full-AQHCD including rotary joint technology, automatic docking technology and precise docking technology for quick action coupling, are concisely expressed. Thirdly, the hydraulic motor driving gear type slewing bearing technology of the turning device made domestically for the main-ACW is introduced, and the hydraulic motor driving worm type slewing bearing technology of the turning device imported from HKS company in Germany for the vice-ACW is presented, especially, the existing gap in the similar domestic technology is discussed. Subsequently, the hydraulic cylinder driving 4-bar linkage technology of the swaying device made domestically for the main-ACW is introduced, and the hydraulic double spiral swing cylinder technology of the swaying device imported from HKS company in Germany for the vice-ACW is presented, especially, the existing gap in the similar domestic technology is discussed. Finally, it is emphasized that these technological gaps have seriously restricted the ability of the vice-ACW to successfully work in future actual rescue combats, therefore, it must be highly valued in the follow-up research and development (R&D) through cooperating with professional manufacturers in China, thereby making technological advances.

Cloning and characterization of the geranylgeranyl diphosphate synthase (GGPS) responsible for carotenoid biosynthesis in Pyropia umbilicalis

Carotenoid metabolism in red algae is not well understood. Geranylgeranyl diphosphate (GGPP), synthesized by GGPP synthase (GGPS), is a precursor for the biosynthesis of many biologically important metabolites, including carotenoids and chlorophylls. GGPSs have been functionally characterized in many organisms, but not in species of the primitive red algal order Bangiales. Here, we cloned and characterized the gene encoding GGPS (PuGGPS) in Pyropia umbilicalis (Bangiales). PuGGPS encodes a protein of 345 amino acids with an N-terminal transit peptide. The catalytic activity of PuGGPS for the production of GGPP was verified by a color complementation assay in Escherichia coli and subsequent high-performance liquid chromatography analysis. Homology modeling of PuGGPS showed that its tertiary structure resembles that of other known GGPSs and that this structure allows for the precise docking of the enzymatic product of PuGGPS, GGPP. When leafy thalli of P. umbilicalis were treated with norflurazon, an inhibitor of the key carotenoid metabolism enzyme phytoene desaturase, the expression of PuGGPS increased by twofold compared with that of the control in the first 2 h, suggesting a prompt response to metabolic perturbation. Prolonged norflurazon treatment failed to increase PuGGPS expression. Sequence analysis showed that PuGGPS shares seven conserved motifs with other previously identified GGPSs from different organisms, including two aspartate-rich GGPS signature motifs. Phylogenetic analysis also indicated that PuGGPS is a member of the type II GGPSs found in eubacteria and plants.

WE‐D‐17A‐02: Evaluation of a Two‐Dimensional Optical Dosimeter On Measuring Lateral Profiles of Proton Pencil Beams

Purpose:To evaluate the accuracy of a two‐dimensional optical dosimeter on measuring lateral profiles for spots and scanned fields of proton pencil beams.Methods:A digital camera with a color image senor was utilized to image proton‐induced scintillations on Gadolinium‐oxysulfide phosphor reflected by a stainless‐steel mirror. Intensities of three colors were summed for each pixel with proper spatial‐resolution calibration. To benchmark this dosimeter, the field size and penumbra for 100mm square fields of singleenergy pencil‐scan protons were measured and compared between this optical dosimeter and an ionization‐chamber profiler. Sigma widths of proton spots in air were measured and compared between this dosimeter and a commercial optical dosimeter. Clinical proton beams with ranges between 80 mm and 300 mm at CDH proton center were used for this benchmark.Results:Pixel resolutions vary 1.5% between two perpendicular axes. For a pencil‐scan field with 302 mm range, measured field sizes and penumbras between two detection systems agreed to 0.5 mm and 0.3 mm, respectively. Sigma widths agree to 0.3 mm between two optical dosimeters for a proton spot with 158 mm range; having widths of 5.76 mm and 5.92 mm for X and Y axes, respectively. Similar agreements were obtained for others beam ranges. This dosimeter was successfully utilizing on mapping the shapes and sizes of proton spots at the technical acceptance of McLaren proton therapy system. Snow‐flake spots seen on images indicated the image sensor having pixels damaged by radiations. Minor variations in intensity between different colors were observed.Conclusions:The accuracy of our dosimeter was in good agreement with other established devices in measuring lateral profiles of pencil‐scan fields and proton spots. A precise docking mechanism for camera was designed to keep aligned optical path while replacing damaged image senor. Causes for minor variations between emitted color lights will be investigated.

Comparative Evolution of four Scoring Functions with Three Models of Delta Opioid Receptor Using Molecular Docking

The present study was performed in order to find the most appropriate scoring functions and the model for docking of enkephalin analogues with delta-opioid receptor (DOR) that correlated well with the results obtained from in vitro tests. The capabilities of the four scoring functions embedded in GOLD were explored with three different models of DOR: a theoretical model published in ePDB (id: 1ozc), a model obtained by as with homology modeling, and a crystal structure of DOR published in PDB (id: 4ej4). Eleven enkephalin analogues were consistently docked with each of the models with each of the four scoring function. The analysis of the obtained results shows that after the docking with our modeled DOR values of scoring functions correlate with the data from in vitro tests at the highest degree. Furthermore, the use of the scoring functions ASP (Astex Statistical Potential) and GoldScore enable more precise docking of the test ligands as correlation coefficients were....

Instantaneous Global Navigation Satellite System (GNSS)-Based Attitude Determination for Maritime Applications

Global Navigation Satellite System (GNSS) is a valuable technology for a large number of maritime applications. Other than providing the absolute positioning service, it aids many demanding applications, such as precise docking, formation of surface craft, autonomous vehicles, sinkage monitoring, etc. GNSS carrier-phase-based algorithms provide high-precision positioning solutions, but an integer number of cycles inherent to the observed signal have to be resolved. A newly developed GNSS carrier-phase ambiguity resolution method is tested. The new method solves for the unknown number of integer cycles by exploiting the known placement of the GNSS antennas aboard the vessel. The a priori information on the antennas baseline separation is employed as a hard constraint. A simplified (linearized) version of the method, suitable for large vessels, is also analyzed. The new method was tested against the most challenging scenario when processing GNSS data: single-frequency, single-epoch, unaided ambiguity resolution. Through different tests, the high performance of the new method is demonstrated: high fixing rate, large robustness, and short time-to-fix after initialization, cycle slips, and/or loss of locks. Considerations about the wide spectra of maritime applications are given, and a specific experiment is carried out to demonstrate the capabilities of the method for navigation in shallow waters.

Numerical Errors and Chaotic Behavior in Docking Simulations

This work examines the sensitivity of docking programs to tiny changes in ligand input files. The results show that nearly identical ligand input structures can produce dramatically different top-scoring docked poses. Even changing the atom order in a ligand input file can produce significantly different poses and scores. In well-behaved cases the docking variations are small and follow a normal distribution around a central pose and score, but in many cases the variations are large and reflect wildly different top scores and binding modes. The docking variations are characterized by statistical methods, and the sensitivity of high-throughput and more precise docking methods are compared. The results demonstrate that part of docking variation is due to numerical sensitivity and potentially chaotic effects in current docking algorithms and not solely due to incomplete ligand conformation and pose searching. These results have major implications for the way docking is currently used for pose prediction, ranking, and virtual screening.

The Ndc80 kinetochore complex forms oligomeric arrays along microtubules.

The Ndc80 complex is a key site of regulated kinetochore-microtubule attachment, but the molecular mechanism underlying its function remains unknown. Here we present a subnanometer resolution cryo-electron microscopy reconstruction of the human Ndc80 complex bound to microtubules, sufficient for precise docking of crystal structures of the component proteins. We find that Ndc80 binds the microtubule with a tubulin monomer repeat, recognizing α- and β-tubulin at both intra- and inter-dimer interfaces in a manner that is sensitive to tubulin conformation. Furthermore, Ndc80 complexes self-associate along protofilaments via interactions mediated by the amino-terminal tail of the Ndc80 protein, the site of phospho-regulation by the Aurora B kinase. Ndc80's mode of interaction with the microtubule and its oligomerization suggest a mechanism by which Aurora B could regulate the stability of load-bearing Ndc80-microtubule attachments.

An Image-based Docking Method for Mobile Robot

A new docking method for mobile robot is proposed. The desired docking state (desired position and orientation) of the robot is defined by a pre-captured reference image. The scale invariant feature transform (SIFT) algorithm and a double direction best bin first (BBF) based feature matching algorithm are used to extract the visual feedback information by matching the current view of the docking station and the reference image. The robot is aligned against the reference image based on a epipole servoing strategy. A centroid tracking is used to avoid the object escaping from the field of view. A random sample consensus (RANSAC) algorithm is used to solve the affine transform between current and reference images, and a control rule at last stage is presented to realize precise docking. No more knowledge of the scene geometry or artificial marks are needed. The experiment results of a realistic indoor environment demonstrate the effectiveness of the proposed method.

Characterization of the β-d-Glucopyranoside Binding Site of the Human Bitter Taste Receptor hTAS2R16

G-protein-coupled receptors mediate the senses of taste, smell, and vision in mammals. Humans recognize thousands of compounds as bitter, and this response is mediated by the hTAS2R family, which is one of the G-protein-coupled receptors composed of only 25 receptors. However, structural information on these receptors is limited. To address the molecular basis of bitter tastant discrimination by the hTAS2Rs, we performed ligand docking simulation and functional analysis using a series of point mutants of hTAS2R16 to identify its binding sites. The docking simulation predicted two candidate binding structures for a salicin-hTAS2R16 complex, and at least seven amino acid residues in transmembrane 3 (TM3), TM5, and TM6 were shown to be involved in ligand recognition. We also identified the probable salicin-hTAS2R16 binding mode using a mutated receptor experiment. This study characterizes the molecular interaction between hTAS2R16 and β-d-glucopyranoside and will also facilitate rational design of bitter blockers.

Combining a genetic algorithm with a linear scaling semiempirical method for protein–ligand docking

In the search for more energetically precise docking methods and to avoid the problem of defining suitable ligand force fields, we have built a software to perform rigid molecular docking by combining a genetic algorithm with a linear scaling semiempirical program. The resulting AlgoGen-DivCon software uses the Divide and Conquer linear scaling methodology to evaluate protein–ligand interaction energies using quantum semiempirical hamiltonians while conformational search is performed by a genetic algorithm which optimizes the position of a mobile ligand relative to a fixed protein system. Tests have been performed to assess the performance of AlgoGen-DivCon. Our results on the docking of 8-azaxanthine, oxonic acid and uric acid in a 700 atom Urate Oxidase model are structurally very similar to known crystallographic structures and prove that it is now possible to perform in a reasonable amount of time molecular dockings of relatively large protein–ligand complexes using a quantum description of the interaction energy.

Modeling the structure of bound peptide ligands to major histocompatibility complex.

In this article, we present a new technique for the rapid and precise docking of peptides to MHC class I and class II receptors. Our docking procedure consists of three steps: (1) peptide residues near the ends of the binding groove are docked by using an efficient pseudo-Brownian rigid body docking procedure followed by (2) loop closure of the intervening backbone structure by satisfaction of spatial constraints, and subsequently, (3) the refinement of the entire backbone and ligand interacting side chains and receptor side chains experiencing atomic clash at the MHC receptor-peptide interface. The method was tested by remodeling of 40 nonredundant complexes of at least 3.00 A resolution for which three-dimensional structural information is available and independently for docking peptides derived from 15 nonredundant complexes into a single template structure. In the first test, 33 out of 40 MHC class I and class II peptides and in the second test, 11 out of 15 MHC-peptide complexes were modeled with a Calpha RMSD < 1.00 A.

NMR-based screening methods for lead discovery.

Diversity and robustness of NMR based screening methods make these techniques highly attractive as tools for drug discovery. Although not all screening techniques discussed here may be applicable to any given target, there is however a good chance that at least one of the described methods will prove productive in finding several medium affinity ligands. A comparison of each of the methods is given in Table 1. For drug targets of molecular weight < 30 kDa SAR by NMR appears to be the method of choice since it yields detailed information about the location of the binding site. It remains to be seen whether 15N-1H-TROSY based screening techniques will prove useful for larger protein targets, especially considering the added effort needed for spectral assignment and the increased complexity due to spectral overlap. Nevertheless, with the application of new cryo-cooled NMR probes, 15N-1H-HSQC based screening can now be considered a high throughput method. Ligand-based NMR screening methods can be used for protein targets of virtually any size, but are restricted in the ligand's binding affinity range. Because sufficient ligand-protein dissociation rates are needed, only binding of ligands with low (milimolar) to intermediate (micromolar) affinities is detectable. It is expected that cryo-cooled NMR probe technology will also advance ligand detected NMR screening to the high throughput level. Certainly protein and ligand concentrations can be lowered drastically and experiment times can be shortened with increased sensitivity. However, spectral overlap will be of major concern when mixtures of up to 100 compounds are to be screened. For such applications only techniques for which the signals of bound ligands survive will be useful, and sophisticated software will be needed to deconvolute the spectra of multiple bound ligands. Although only ligands with medium to low affinities can be found, ligand based NMR screening has been used as an effective prescreening tool for assay based high throughput screening. Identifying a large ensemble of medium affinity ligands may not only aid in building a binding site pharmacophore model (see Chapter 11), but also may yield crucial information for overcoming tissue availability, toxicity, or even intellectual property related problems. Although NMR based screening is only one of the more recent additions to the bag of tools used in drug discovery [1, 2], its simplicity and wide range of application (including protein-protein and protein-nucleic acid interactions) has attracted much attention. Advances in NMR instrumentation and methodology have already paved the road for NMR based screening to become a high throughput technique. In addition to this, NMR is exceptional in the amount of detailed structural [table: see text] information it can provide. Not only can NMR readily reveal the binding site (15N-1H-HSQC screening) or the conformation of the bound ligand (transfer NOE), but it can also supply information that enables precise docking of the ligand to the protein's binding pocket (isotope-filtered NOESY). NMR data can therefore provide a natural connection between experimental HTS and combinatorial chemistry techniques with computational methods such as 3D-database searching (see Chapter 10), virtual screening (docking) and structure-based ligand design (see also Chapter 8).

Molecular simulation reveals structural determinants of the hanatoxin binding in Kv2.1 channels.

The carboxyl terminus of the S3 segment (S3C) in voltage-gated potassium channels was suggested to be the binding site of gating modifier toxins like hanatoxin. It has also been proposed to have a helical secondary structural arrangement. The currently available structures in high resolution for such channel molecules are restricted to regions illustrating the pore function. Therefore no further direct experimental data to elucidate the detailed mechanism for such toxin binding can be derived. In order to examine the putative three-dimensional structure of S3C and to analyze the residues required for hanatoxin binding, molecular simulation and docking were performed, based on the solution structure of hanatoxin and the structural information from mutational scanning data for the S3C fragment in Kv2.1. Our results indicate that hydrophobic and electrostatic interactions are both utilized to stabilize the toxin binding. Precise docking residues and the appropriate orientation for binding regarding amphipathic environments are also described. Compared with the functional data proposed by previous studies, the helical structural arrangement for the C-terminus of the S3 segment in voltage-gated potassium channels can therefore be further emphasized and analyzed. The possible location/orientation for toxin binding with respect to membrane distribution around the S3C segment is also discussed in this paper.

Geno-fuzzy control in autonomous servicing of a space station

The provision of spacecraft servicing to a space station comprises the tasks of assembly, resupply, repair and maintenance of manufactured space parts in-orbit. Servicing tasks use rendezvous and docking operations to accomplish their objectives. Autonomous servicing relies on intelligent fly control systems to perform fast, soft, and precise docking operations. This paper proposes the use of a fuzzy logic control system, mounted on an active chaser vehicle which wants to dock with a big passive space station in orbit around the Earth. The geno-fuzzy controller is a knowledge-based controller that performs the closed-loop operations autonomously. It produces smooth control actions in the proximity of the target and during the docking, to avoid disturbance torques in the final assembly orbit. The use of a genetic algorithm tool to optimise the controller so as to reduce docking time and fuel consumption is analyzed. It performs the optimization by finding the best fuzzy sets of the controller membership functions, and the most suitable rule data base.

A Different Method for Steric Field Evaluation in CoMFA Improves Model Robustness

The all-grid probe Lennard-Jones 6−12 potential, typically used as steric descriptor in CoMFA, has been replaced by the volumes of van der Waals envelopes intersections between the probe-atom and the ligand molecules under investigation. The intersection volumes present a smoother distance dependence that overcomes the problems arising from formulation of a precise alignment and docking into the 3D lattice. A CoMFA-type application on a set of 78 steroid aromatase inhibitors with different grid and probe-atom characteristics suggests an improved model robustness for the new steric field in comparison with the classical 6−12 potential. Predefined cut-off and “minimum sigma” values are not required. Systematic variation of the 3D lattice position leads to lower variations of cross-validated r-squared (q2LOO) at all levels of model complexity, which can be reduced with exclusion of some “interior” points. The relative simplicity and inexpensive computational demands make this steric field a promising altern...

Geno-Fuzzy Control of Spacecraft Automatic Servicing

Spacecraft servicing comprises the tasks of assembly, resupply, repair and maintenance of in-orbit manufactured space parts. Automatic servicing relies on intelligent fly control systems to perform fast, soft, and precise docking operations. This paper proposes the use of a fuzzy logic guidance and navigation system mounted on an active chaser vehicle, which wants to dock with a big passive space station on orbit around the Earth. It produces smooth control actions in the proximity of the target, and during the docking to avoid disturbance torques in the final assembly orbit. A genetic algorithms tool is used to optimize the controller reducing docking time, and fuel consumption. It performs the optimization by finding the best fuzzy sets, and membership functions of the controller.

Rapid, electrostatically assisted association of proteins

The rapid association of barnase and its intracellular inhibitor barstar has been analysed from the effects of mutagenesis and electrostatic screening. A basal association rate constant of 10(5) M(-1) s(-1) is increased to over 5 x 10(9) M(-1) s(-1) by electrostatic forces. The association between the oppositely charged proteins proceeds through the rate-determining formation of an early, weakly specific complex, which is dominated by long-range electrostatic interactions, followed by precise docking to form the high affinity complex. This mode of binding is likely to be used widely in nature to increase association rate constants between molecules and its principles may be used for protein design.