Active-site-directed 3D database searching: Pharmacophore extraction and validation of hits

Summary Two new computational tools, PRO_PHARMEX and PRO_SCOPE, for use in active-site-directed searching of 3D databases are described. PRO_PHARMEX is a flexible, graphics-based program facilitating the extraction of pharmacophores from the active site of a target macromolecule. These pharmacophores can then be used to search a variety of databases for novel lead compounds. Such searches can often generate many hits of varying quality. To aid the user in setting priorities for purchase, synthesis or testing, PRO_SCOPE can be used to dock molecules rapidly back into the active site and to assign them a score using an empirical scoring function correlated to the free energy of binding. To illustrate how these tools can add value to existing 3D database software, their use in the design of novel thrombin inhibitors is described.     

Development of Advanced Software Tools for Computer‐Aided Design,Simulation, and Optimization of Polymerization Processes

A new software has been developed for the simulation, design, parameter and state estimation, optimization, and control of specific polymerization processes aiming at increasing plant efficiency, improving product quality, and reducing the impact to environment. It provides a user‐friendly interface, including a design environment that can be accessed from the engineer's desktop computer, allowing graphical interaction and expert system guidance on how to use the program or make engineering decisions. The software design allows the collection of models from different sources leading to an easy and comprehensive synthesis of process models. Recent advances regarding the development of software applications for three specific polymerization systems are presented.

     

A software package for the evaluation of Zeeman AAS data using a Perkin-Elmer model 3600 data station

The Perkin-Elmer Zeeman/5000 Atomic Absorption Spectrometer is only able to perform a calibration with three single standards or a one-point standard addition. The accuracy and precision of these methods are inappropriate in ETA-AAS, a computer-based data management is essential.A software package for calibration and evaluation was developed using curve fitting by linear regression based on a leastsquares fit when absorbances were transformed by the Baule-Mitscherlich function. The total analytical range could be covered by this method whether peak area or peak height values were fitted. The maximum absorbance levels could be calculated, as well.Absorbance signals were collected and stored by the HGA-graphics software (modified by Perkin-Elmer Nederland B. V.). The Pecowriter software was used for identifying data and file manipulations. The results of the calibration and evaluation can be stored on disk and/or printed. Calibration curves can be plotted on hardcopy output. The Limit of Detection and the Characteristic Mass can be calculated.The use of the CALIBRATION program is demonstrated by the calibration curves for the determination of Pb, Cd, As, Se, Cr, Al, Cu and Ni using mostly STPF-conditions. The performance of the method evaluated by the root mean square percent deviation of the fit is equal to the traditional curve-fitting function as well as to rational or quadratic functions.The use of the EVALUATION program is demonstrated by the results of the direct determination of lead in mineral waters.     

PRO_LIGAND: An approach to de novo molecular design. 6. Flexible fitting in the design of peptides

Summary This paper describes the further development of the functionality of our in-house de novo design program, PRO_LIGAND. In particular, attention is focussed on the implementation and validation of the directed tweak method for the construction of conformationally flexible molecules, such as peptides, from molecular fragments. This flexible fitting method is compared to the original method based on libraries of prestored conformations for each fragment. It is shown that the directed tweak method produces results of comparable quality, with significant time savings. By removing the need to generate a set of representative conformers for any new library fragment, the flexible fitting method increases the speed and simplicity with which new fragments can be included in a fragment library and also reduces the disk space required for library storage. A further improvement to the molecular construction process within PRO_LIGAND is the inclusion of a constrained minimisation procedure which relaxes fragments onto the design model and can be used to reject highly strained structures during the structure generation phase. This relaxation is shown to be very useful in simple test cases, but restricts diversity for more realistic examples. The advantages and disadvantages of these additions to the PRO_LIGAND methodology are illustrated by three examples: similar design to an alpha helix region of dihydrofolate reductase, complementary design to the active site of HIV-1 protease and similar design to an epitope region of lysozyme.     

Design and Application of an Easy to Use Oligonucleotide Mass Calculation Program

With the development of new synthesis procedures, an ever increasing number of chemical modifications can now be incorporated into synthetic oligonucleotides, representing new challenges for analytical chemists to efficiently identify and characterize such molecules. While conventional mass spectrometry (MS) has proven to be a powerful tool to study nucleic acids, new and improved methods and software are now needed to address this emerging challenge. In this report, we describe a simple yet powerful program that affords great flexibility in the calculation of theoretical masses for conventional as well as modified oligonucleotide molecules. This easy to use program can accept input oligonucleotide sequences and then calculate the theoretical mass values for full length products, process impurities, potential metabolites, and gas phase fragments. We intentionally designed this software so that modified nucleotide residues can be incorporated into oligonucleotide sequences, and corresponding mass values can be rapidly calculated. To test the utility of this program, two oligonucleotides that contain a large number of chemical modifications were synthesized. We have analyzed these samples using a Q-TOF mass spectrometer and compared the calculated masses to the observed ones. We found that all of the data matched very well with less than 30 ppm mass errors, well within the expectation for our instrument operated in its current mode. These data confirmed the validity of calculations performed with this new software.

NADA: A versatile PC based program for neutron activation data analysis

We have developed a PC based program for neutron activation data analysis using the FORTRAN and C languages. The routines are based on creating files associated with conventional ORTEC hardware and output software. The main features of the program include radionuclide identification, and the use of semi-automatic integration or the peak fitting SAMPO routine. Other developments are hard and soft copy records for detailed sample identification and particular irradiation, decay and counting procedures. Flux variations, high deadtime corrections, counting geometries, spectral and nuclear interferences, as well as uranium fission interferences are also automatically accounted for. The data output includes concentration values in %, ppm, g or ppb units with associated errors, while detection limits for each individual sample are indicated. Further data output can easily be generated which can be imported to most spreadsheet programs for various statistical uses. A future implementation to the program will include batch-file processing and automated self-absorption calculations for geological samples.     

Molecular docking studies of a group of hydroxamate inhibitors with gelatinase-A by molecular dynamics

We have performed docking and molecular dynamics simulations of hydroxamates complexed with human gelatinase-A (MMP-2) to gain insight into the structural and energetic preferences of these inhibitors. The study was conducted on a selected set of eleven compounds with variation in structure and activity. Molecular dynamics simulations were performed at 300 K for 100 ps with equilibration for 50 ps. The structural analyses of the trajectories indicate that the coordinate bond interactions, the hydrogen bond interactions, the van der Waals interactions as well as the hydrophobic interactions between ligand and receptor are responsible simultaneously for the preference of inhibition and potency. The ligand hydroxamate group is coordinated to the catalytic zinc ion and form stable hydrogen bonds with the carbonyl oxygen of Gly 162. The P1 group makes extensive van der Waals and hydrophobic contacts with the nonpolar side chains of several residues in the S1 subsite, including Leu 197, Val 198, Leu 218 and Tyr 223. Moreover, four to eight hydrogen bonds between hydroxamates and MMP-2 are formed to stabilize the inhibitors in the active site. Compared with the P2 and P3 groups, the P1 groups of inhibitors are oriented regularly, which is produced by the restrain of the S1 subsite. From the relationship between the length of the nonpolar P1 group and the biological activity, we confirm that MMP-2 has a pocket-like S1 subsite, not a channel-like S1 subsite proposed by Kiyama (Kiyama, R. et al., J. Med. Chem. 42 (1999), 1723). The energetic analyses show that the experimental binding free energies can be well correlated with the interactions between the inhibitors and their environments, which could be used as a simple score function to evaluate the binding affinities for other similar hydroxamates. The validity of the force field parameters and the MD simulations can be fully testified by the satisfactory agreements between the experimental structure-activity relationship and the information from the structural and energetic analyses. The information generated from the predicted complexes should be useful for further work in the area of structure-based design of new compounds.     

The program “MULTINAA” for various standardization methods in neutron activation analysis

A compute program MULTINAA was developed to facilitate the evaluation of NAA data. It is written for the VAX/VMS syste and opeates in the Canberra/ND Genie spectroscopy software environment. MULTIINAA can be appliede to relative,k ₀-, monostandard (modified) and absolute methods, including the fast neutron threshold reaction. For each calculation, the available standardizations can be used individually or mixed. In all the standardization modes MULTINAA fetches the data directly from the -ray spectra and libraries, thus reducing the manual work to a minimum. MULTINAA is flexibkle to meet various situations in NAA practical work. The required neutron flux parameters all the non-relative methods are supplied by an accompanying program MULTIFLUX.     

Design criteria for molecular mimics of fragments of the β-turn. 1. Cα atom analysis

Peptides represent an extensive class of biologically active molecules. They may be used as leads in the development of novel therapeutic agents provided the pharmacophoric information present within them can be translated into non-peptide analogs that lack the peptide backbone and are stable to proteolysis. This is the rationale for peptidomimetic drug design. Frequently, the -turn has been implicated as a conformation important for biological recognition of peptides. Empirical evidence from known peptidomimetics, coupled with a theoretical model of peptide binding and the observation that glycine and proline residues are common within the -turn, has suggested the design of molecules to mimic placement of between two and four of the side-chains. The moderate number of different -turn conformations, combined with the combinatoric nature of side-chain selection complicates the procedure. In this paper, cluster analysis has been used to classify the arrangement of C_{_} atoms about the various fragments of the -turn. Recombination of the observed patterns provides a general model for the -turn which may be used as an effective screen for potential peptidomimetic scaffolds in chemical databases.     

Quality management education over the Internet

We describe a program for continuing education in Quality management and metrology. It may be followed by class lectures, by videoconference or by individual distance learning over the Internet. An important feature for students who attend classes is visits to selected institutions for demonstrations of quality management in practice. For students using distance learning, multimedia presentations containing a total of 2 h of video and supporting documentation is the alternative to the visits. The program is aimed at personnel from all fields, and its emphasis is on the generality of quality principles, attitudes and motivation for quality thinking, measurements in quality work, as well as the use of system audits and other elements of quality management in related fields.     

An Algorithm Based on Simple Rules for the Determination of the Architecture of Branched Polymer Molecules from the Number of Branching Points per Molecule

A general simple algorithm is proposed to determine the average architecture of an acyclic branched polymer macromolecule from its number of branching points, whatever their functionality. The number of branching points can be derived from SEC measurements using a coupling of viscosimetric and refractometric detectors through the use of the Zimm‐Stockmayer equation. Since various isomers can be built for a given number of branching points, some basic rules are proposed in order to select the structures that are physically meaningful; the possibility of structural isomers has been also investigated and a probability of presence is assigned to each species starting from the compactness of the molecule. For each species corresponding to a given molecular weight in the sample, the average structure is then obtained from the number of branching points and the universal probability distribution of the isomers.

     

Automated molecular design: A new fragment-joining algorithm

Summary A popular first step in the problem of structure-based, de novo molecule design is to identify regions where specific functional groups or chemical entities would be expected to interact strongly. When the three-dimensional structure of the receptor is not available, it may be possible to derive a pharmacophore giving the three-dimensional relationships between such chemical groups. The task then is to design synthetically feasible molecules which not only contain the required groups, but which can also position them in the desired relative orientation. One way to do this is to first link the groups using an acyclic chain. We have investigated the application of the tweak algorithm [Shenkin, P.S. et al., Biopolymers, 26 (1987) 2053] for generating families of acyclic linkers. These linking structures can subsequently be braced using a ring-joining algorithm [Leach, A.R. and Lewis, R.A., J. Comput. Chem., 15 (1994) 233], giving rise to an even wider variety of molecular skeletons for further studies.     

BatteryDataExtractor: battery-aware text-mining software embedded with BERT models

Due to the massive growth of scientific publications, literature mining is becoming increasingly popular for researchers to thoroughly explore scientific text and extract such data to create new databases or augment existing databases. Efforts in literature-mining software design and implementation have improved text-mining productivity, but most of the toolkits that mine text are based on traditional machine-learning-algorithms which hinder the performance of downstream text-mining tasks. Natural-language processing (NLP) and text-mining technologies have seen a rapid development since the release of transformer models, such as bidirectional encoder representations from transformers (BERT). Upgrading rule-based or machine-learning-based literature-mining toolkits by embedding transformer models into the software is therefore likely to improve their text-mining performance. To this end, we release a Python-based literature-mining toolkit for the field of battery materials, BatteryDataExtractor, which involves the embedding of BatteryBERT models in its automated data-extraction pipeline. This pipeline employs BERT models for token-classification tasks, such as abbreviation detection, part-of-speech tagging, and chemical-named-entity recognition, as well as new double-turn question-answering data-extraction models for auto-generating repositories of inter-related material and property data as well as general information. We demonstrate that BatteryDataExtractor exhibits state-of-the-art performance on the evaluation data sets for both token classification and automated data extraction. To aid the use of BatteryDataExtractor, its code is provided as open-source software, with associated documentation to serve as a user guide.

BatteryDataExtractor is the first property-specific text-mining tool for auto-generating databases of materials and their property, device, and associated characteristics. The software has been constructed by embedding the BatteryBERT model.     

Predicting relative binding affinities of non-peptide HIV protease inhibitors with free energy perturbation calculations

The relative binding free energies in HIV protease of haloperidol thioketal (THK) and three of its derivatives were examined with free energy calculations. THK is a weak inhibitor (IC50 = 15 M) for which two cocrystal structures with HIV type 1 proteases have been solved [Rutenber, E. et al., J. Biol. Chem., 268 (1993) 15343]. A THK derivative with a phenyl group on C2 of the piperidine ring was expected to be a poor inhibitor based on experiments with haloperidol ketal and its 2- phenyl derivative (Caldera, P., personal communication). Our calculations predict that a 5-phenyl THK derivative, suggested based on examination of the crystal structure, will bind significantly better than THK. Although there are large error bars as estimated from hysteresis, the calculations predict that the 5-phenyl substituent is clearly favored over the 2-phenyl derivative as well as the parent compound. The unfavorable free energies of solvation of both phenyl THK derivatives relative to the parent compound contributed to their predicted binding free energies. In a third simulation, the change in binding free energy for 5-benzyl THK relative to THK was calculated. Although this derivative has a lower free energy in the protein, its decreased free energy of solvation increases the predicted G(bind) to the same range as that of the 2-phenyl derivative.     

HyperLab: A new concept in gamma-ray spectrum analysis

HyperLab is a new Ge gamma-ray analysis code for MS Windows, developed using object-oriented design. The novel feature of the program is the extensive use of relational database technology, which allows the efficient storage and handling of any digital data encountered in gamma-ray spectroscopy. While preserving the main concept of the predecessors (HYPERMET and its derivatives) for semi-automatic analysis of multichannel pulse-height spectra, the substantially reshaped basic routines vastly improved the stability and reliability of peak fitting. New features include the fitting of peaks with high energy tail, as well as library-directed Graphical Isotope Identification. Procedures for efficiency, nonlinearity, etc. calibrations are now highly automated. By exploiting all the benefits of MS Windows technology (point-and-click simplicity in task executions, intelligent mouse pointer, etc.) HyperLab is a versatile and user-friendly tool which the discriminating spectroscopist will find of great value.     

“Living” Radical Polymerization in Tubular Reactors, 2 – Process Optimization for Tailor‐Made Molecular Weight Distributions

“Living” radical polymerization is a relatively new polymerization process that can be used to prepare resins with controlled structures. In this work, a mathematical model developed previously to describe nitroxide‐mediated “living” radical polymerizations performed in tubular reactors is used for the optimization of the process and obtainment of tailor‐made MWDs. Operating conditions and design variables are determined with the help of optimization procedures in order to produce polymers with specified MWDs. It is shown that bimodal and trimodal MWDs, with given peak locations, can be obtained through proper manipulation of the operating conditions. This indicates that the technique discussed in this work is suitable for detailed design of the MWD of the final polymer.

     

Matching organic libraries with protein-substructures

We present a general approach which allows automatic identification of sub-structures in proteins that resemble given three-dimensional templates. This paper documents its success with non-peptide templates such as -turn mimetics. We considered well-tested turn-mimetics such as the bicyclic turned dipeptide (BTD), spiro lactam (Spiro) and the 2,5-disubstituded tetrahydrofuran (THF), a new furan-derivative which was recently developed and characterized. The detected geometric similarity between the templates and the protein patches corresponds to r.m.s.-values of 0.3 Å for more than 80% of the constituting atoms, which is typical for active site comparisons of homologous proteins. This fast automatic procedure might be of biomedical value for finding special mimicking leads for particular protein sub-structures as well as for template-assembled synthetic protein (TASP) design.     

Effect of the Molecular Weights of Poly‐L‐Arginine on Membrane Strength and Permeability of Poly‐L‐Arginine Group Microcapsules

A novel poly‐L ‐arginine group microcapsule was produced to investigate its nutritional function and pharmacological efficacy. The molecular weight of poly‐L ‐arginine is an important parameter for its membrane strength, but does not obviously affect its release property. Thus, poly‐L ‐arginine can be used as a kind of new membrane material in microcapsules, and it is expected to be used as an therapeutic and biodegradable drug carrier.

Influence of the molecular weight of poly‐L ‐arginine on membrane thickness.     

DynamO: a free O(N) general event-driven molecular dynamics simulator

Molecular dynamics algorithms for systems of particles interacting through discrete or "hard" potentials are fundamentally different to the methods for continuous or "soft" potential systems. Although many software packages have been developed for continuous potential systems, software for discrete potential systems based on event-driven algorithms are relatively scarce and specialized. We present DynamO, a general event-driven simulation package, which displays the optimal O(N) asymptotic scaling of the computational cost with the number of particles N, rather than the O(N) scaling found in most standard algorithms. DynamO provides reference implementations of the best available event-driven algorithms. These techniques allow the rapid simulation of both complex and large (>10(6) particles) systems for long times. The performance of the program is benchmarked for elastic hard sphere systems, homogeneous cooling and sheared inelastic hard spheres, and equilibrium Lennard-Jones fluids. This software and its documentation are distributed under the GNU General Public license and can be freely downloaded from http://marcusbannerman.co.uk/dynamo.