Plate-based diversity subset screening generation 2: an improved paradigm for high-throughput screening of large compound files

High-throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time consuming and costly and the use of subsets as an efficient alternative to screening entire compound collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity or biological target focus. Previously, we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second-generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer.     

Leadlikeness and structural diversity of synthetic screening libraries

Summary High program failure rates in the pharmaceutical industry have prompted the development of predictive software that can profile compound libraries as being ‘druglike’ (resembling existing drugs) and/or ‘leadlike’ (possessing the structural and physicochemical profile of a quality lead). In recent years, these two notions prompted pharmaceutical companies to clean up their corporate libraries of screening compounds. In order to maintain and expand the size and diversity of these corporate libraries, pharmaceutical companies still continue to add compounds to these, mainly by the acquisition of screening libraries. In this paper, we have analyzed 45 commercially available libraries, offered by suppliers of screening chemistry, for leadlikeness and diversity of the offered structures. To this end we have used a set of structural and physicochemical filters for leadlikeness that was developed in-house. These 45 supplier libraries contained a total of 5.3 million structures, of which 49% (2,592,778 structures) turned out to be unique, and only 12% (677,328 structures) were found to be both unique and leadlike. A diversity analysis revealed that big differences exist between the various offered libraries.     

A reagent-based strategy for the design of large combinatorial libraries: A preliminary experimental validation

Combinatorial library design can be carried out at either the reagent or the product level. Various reports in the literature have come to conflicting conclusions in favor of one over the other. In this paper a reagent-based screening library design strategy is presented. The method relies on analysis of scaffolds and building blocks separately to define the overall diversity in a compound file. The primary diversity selection by properties relevant for molecular recognition and by redundancy is followed by the application of filters for molecular properties known to be relevant for drug-likeness. Filter properties are rapidly estimated at the product level using a fragmental estimation approach. Initial experimental data suggest that high diversity in vast screening libraries can be achieved by carefully applied reagent level analysis. A potential role of diverse screening libraries in chemical genomics (pharmacological knockouts) is also discussed.     

In silico design of chiral dimers to direct the synthesis of a chiral zeolite

ABSTRACT

We have applied in silico materials design in an effort to design chiral organic structure directing agents (OSDAs) for the synthesis of enantiomerically enriched STW zeolite. To do so, we have used both exhaustive virtual screening of a limited set of symmetrical imidazolium dimers and a multi-objective genetic algorithm to effectively search a larger virtual combinatorial chemistry space that is too vast for an exhaustive approach.     

Future pathways for combinatorial chemistry

Summary Investment in combinatorial chemistry (combichem) in the pharmaceutical industry is being driven by the need for increased efficiency. Results from pioneers in the field have demonstrated where mixture or discrete compound synthesis is useful, and what mixture sizes and compound concentrations are appropriate. To make the techniques of combichem of general utility in drug discovery, a broad range of advances is still required. Conversion of organic chemistry to solid phase conditions is key, as are developments in linkers and resins. Library design methodology requires further development. Combinatorial biosynthesis of focused libraries of natural products holds great promise for capitalising on hardwon natural product leads. Miniaturisation of screens is required to reduce the cost of screening combinatorial libraries. Developments in the processes preceding and following synthesis are required to enable the flow of increased numbers of compounds without new bottlenecks developing. The impact of combinatorial chemistry will be greatly enhanced by synergy with ongoing parallel developments in genetic technologies, screening technologies and bioinformatics.     

LBVS: an online platform for ligand-based virtual screening using publicly accessible databases

Abundant data on compound bioactivity and publicly accessible chemical databases increase opportunities for ligand-based drug discovery. In order to make full use of the data, an online platform for ligand-based virtual screening (LBVS) using publicly accessible databases has been developed. LBVS adopts Bayesian learning approach to create virtual screening models because of its noise tolerance, speed, and efficiency in extracting knowledge from data. LBVS currently includes data derived from BindingDB and ChEMBL. Three validation approaches have been employed to evaluate the virtual screening models created from LBVS. The tenfold cross validation results of twenty different LBVS models demonstrate that LBVS achieves an average AUC value of 0.86. Our internal and external testing results indicate that LBVS is predictive for lead identifications. LBVS can be publicly accessed at http://rcdd.sysu.edu.cn/lbvs.     

Design of chemical libraries with potentially bioactive molecules applying a maximum common substructure concept

Success in small molecule screening relies heavily on the preselection of compounds. Here, we present a strategy for the enrichment of chemical libraries with potentially bioactive compounds integrating the collected knowledge of medicinal chemistry. Employing a genetic algorithm, substructures typically occurring in bioactive compounds were identified using the World Drug Index. Availability of compounds containing the selected substructures was analysed in vendor libraries, and the substructure-specific sublibraries were assembled. Compounds containing reactive, undesired functional groups were omitted. Using a diversity filter for both physico-chemical properties and the substructure composition, the compounds of all the sublibraries were ranked. Accordingly, a screening collection of 16,671 compounds was selected. Diversity and chemical space coverage of the collection indicate that it is highly diverse and well-placed in the chemical space spanned by bioactive compounds. Furthermore, secondary assay-validated hits presented in this study show the practical relevance of our library design strategy.     

IR spectral depth profiling using fourier transform photothermal beam deflection

FTIR photothermal beam-deflection spectroscopy (PBDS) was used to make spectral depth-profiling measurements with synthetic bilayer samples of polyethylene/nitrocellulose, with a commercial plastic having surface printing and with a single human hair. A Digilab interferometer modified to operate at several scan speeds was used to record the spectra, without the cell-resonance problems found with photoacoustic spectroscopy (PAS). The utility of spectral depth profiling is discussed; significant S/N improvements seem to be needed and, with either PBDS or PAS, a wider range of modulation frequencies is required for the methods to be useful.     

Application of computer assisted combinatorial chemistry in antivirial,antimalarial and anticancer agents design

Combinatorial chemistry and technologies have been developed to a stage where synthetic schemes are available for generation of a large variety of organic molecules. The innovative concept of combinatorial design assumes that screening of a large and diverse library of compounds will increase the probability of finding an active analogue among the compounds tested. Since the rate at which libraries are screened for activity currently constitutes a limitation to the use of combinatorial technologies, it is important to be selective about the number of compounds to be synthesized. Early experience with combinatorial chemistry indicated that chemical diversity alone did not result in a significant increase in the number of generated lead compounds. Emphasis has therefore been increasingly put on the use of computer assisted combinatorial chemical techniques. Computational methods are valuable in the design of virtual libraries of molecular models. Selection strategies based on computed physicochemical properties of the models or of a target compound are introduced to reduce the time and costs of library synthesis and screening. In addition, computational structure-based library focusing methods can be used to perform in silico screening of the activity of Compounds against a target receptor by docking the ligands into the receptor model. Three case studies are discussed dealing with the design of targeted combinatorial libraries of inhibitors of HIV-1 protease, P. falciparum plasmepsin and human urokinase as potential antivirial, antimalarial and anti-cancer drugs. These illustrate library focusing strategies.     

Nonlinear screening in multilayer graphene systems

Electrostatic screening in multilayer graphene is highly nonlinear due to the vanishing density of states at the Fermi level. Using a discrete model we study the charge screening normal to the layers. Our model shows a strong charge and temperature dependence and has a simple continuum limit at T=0 for undoped systems. Doped systems can exhibit more complex behavior due to minority-carrier screening. Most importantly we find that the screening length can vary more than an order of magnitude depending on the experimental conditions, reconciling the large range of screening lengths reported in previous experiments. This has important consequences for technological applications of multilayer graphene used in electrodes or transistor channels.     

Measurements of flux-dependent screening in aharonov-bohm rings

In order to investigate the effect of electronic phase coherence on screening we have measured the flux-dependent polarizability of isolated mesoscopic rings at 350 MHz. At low temperatures (below 100 mK) both the nondissipative and the dissipative parts of the polarizability exhibit flux oscillations with a period of one-half a flux quantum in a ring. The sign and amplitude of the effect are in good agreement with recent theoretical predictions. The observed positive magnetopolarizability corresponds to an enhancement of screening when time reversal symmetry is broken. The effect of electronic density and temperature are also measured.     

Destination state screening of active spaces in spin dynamics simulations

We propose a novel avenue for state space reduction in time domain Liouville space spin dynamics simulations, using detectability as a selection criterion--only those states that evolve into or affect other detectable states are kept in the simulation. This basis reduction procedure (referred to as destination state screening) is formally exact and can be applied on top of the existing state space restriction techniques. As demonstrated below, in many cases this results in further reduction of matrix dimension, leading to considerable acceleration of many spin dynamics simulation types. Destination state screening is implemented in the latest version of the Spinach library (http://spindynamics.org).     

Extraordinary sound screening in perforated plates

We report extraordinary effects in the transmission of sound through periodically perforated plates, supported by both measurements and theory. In agreement with recent observations in slit arrays, M. H. Lu et al. [Phys. Rev. Lett. 99, 174301 (2007)10.1103/PhysRevLett.99.174301], nearly full transmission is observed at certain resonant frequencies, pointing out similarities of the acoustic phenomena and their optical counterpart. However, acoustic screening well beyond that predicted by the mass law is achieved over a wide range of wavelengths in the vicinity of the period of the array, resulting in fundamentally unique behavior of the sound as compared to light.     

Is there screening in turbulence?

The statistical mechanics of some electric models predicts exponential decay of space correlations (screening). This suggests that one look also for screening in 2- and 3-dimensional hydrodynamic turbulence.     

An efficient multistep ligand-based virtual screening approach for GPR40 agonists

G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFAR1) is a member of the GPCR superfamily, and GPR40 agonists have therapeutic potential for type 2 diabetes. With the crystal structure of GPR40 currently unavailable, various ligand-based virtual screening approaches can be applied to identify novel agonists of GPR40. It is known that each ligand-based method has its own advantages and limitations. To improve the efficiency of individual ligand-based methods, an efficient multistep ligand-based virtual screening approach is presented in this study, including the pharmacophore-based screening, physicochemical property filtering, protein–ligand interaction fingerprint similarity analysis, and 2D-fingerprint structural similarity search. A focused decoy library was generated and used to evaluate the efficiency of this virtual screening protocol. This multistep workflow not only significantly improved the hit rate compared with each individual ligand-based method, but also identified diverse known actives from decoys. This protocol may serve as an efficient virtual screening tool for the targets without crystal structures available to discover novel active compounds.     

Designing solar-cell absorber materials through computational high-throughput screening

Although the efficiency of CH_3 NH_3 PI_3 has been refreshed to 25.2%,stability and toxicity remain the main challenges for its applications.The search for novel solar-cell absorbers that are highly stable,non-toxic,inexpensive,and highly efficient is now a viable research focus.In this review,we summarize our recent research into the high-throughput screening and materials design of solar-cell absorbers,including single perovskites,double perovskites,and materials beyond Perovskites.BazrS_3(single perovskite),Ba_2 BiNbS_6(double perovskite),HgAl_2 Se_4(spinel),and IrSb_3(skutterudite)were discovered to be potential candidates in terms of their high stabilities,appropriate bandgaps,small carrier effective masses,and strong optical absorption.     

Fourier treatment to the diffractive optical element composed of Fresnel zone and pinholes

Currently, the minimum feature size fabricated is about 15-40 nm. The resolution of Fresnel zone plates is limited by the width of the outermost zone. Although the photon sieves make it possible to focus soft X-rays to spot sizes smaller than the diameter of the smallest pinhole they have low diffraction efficiency. In order to foster strengths and circumvent weaknesses of them, we propose a new model which is composed of Fresnel zone and pinholes and give its fast Fourier algorithm. The simulation results demonstrate that the resolution of photon sieves is not better than that of Fresnel zone plates in low order of local rings. In this case, we can substitute pinholes for Fresnel zone in photon sieves. Resolution is nearly a constant, and also the diffraction efficiency improves.     

Study on the pre-chopper in CSNS LEBT

Physical designing of the pre-chopper in CSNS LEBT is carried out,which includes the deflecting voltage,the length and the width of the deflecting plates,and the gap between the deflecting plates.The most outstanding feature of the design is that both the gap and the width vary with the beam envelope size.So both the requried deflecting voltage and the loaded capacitance are lowered.In order to avoid destruction of the space charge neutralization by the pre-chopper in the whole LEBT,an electron-trapping electrode is arranged to confine the electrostatic field of the pre-chopper to the local area.To examine the reliability of the pre-chopping design in CSNS LEBT,a similar pre-chopping design in ADS RFQ LEBT is set up and an experiment on the pre-chopper is prepared.3-dimensional simulations are carried out to determine the loaded capacitance and the applied voltage of the electron-trapping electrode.