A scalable approach to combinatorial library design for drug discovery

In this paper, we propose an algorithm for the design of lead generation libraries required in combinatorial drug discovery. This algorithm addresses simultaneously the two key criteria of diversity and representativeness of compounds in the resulting library and is computationally efficient when applied to a large class of lead generation design problems. At the same time, additional constraints on experimental resources are also incorporated in the framework presented in this paper. A computationally efficient scalable algorithm is developed, where the ability of the deterministic annealing algorithm to identify clusters is exploited to truncate computations over the entire data set to computations over individual clusters. An analysis of this algorithm quantifies the tradeoff between the error due to truncation and computational effort. Results applied on test data sets corroborate the analysis and show improvement by factors as large as 10 or more, depending on the data sets.     

A solid phase approach to PDMP analogs：A general strategy for combinatorial library

The present work reports the first solid phase synthesis of biologically interesting D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol(D-threo-PDMP)derivatives.This synthetic strategy includes facile preparation of versatile azido intermediate(5) in a relatively short sequence and the subsequent derivatization of 5,which led to a series of sulfonamide,urea and heterocycle substituted PDMP analogs(10 and 10’).With this method,a 5280-member compound library has been successfully built by IRORI Nanokan? system.     

Sensitivity analysis and other improvements to tailored combinatorial library design

"Tailoring" combinatorial libraries was developed several years ago as a very general and intuitive method to design diverse compound collections while controlling the profile of other pharmaceutically relevant properties. The candidate substituents were assigned to "categorical bins" according to their properties, and successive steps of D-optimal design were performed to generate diverse substituent sets consistent with required membership quotas from each bin. This serial algorithm was expedient to implement from existing D-optimal design codes, but was order-dependent and did not generally locate the very best possible design. A new "parallel" Fedorov search algorithm has now been implemented that can find the most diverse property-tailored design. An ambiguous mass penalty has been added, whereby most duplicate masses can be eliminated with little loss of library diversity. Sensitivity analysis has also been added to quantitatively explore the diversity trade-offs due to increasing or decreasing each specific kind of bias.     

OptDesign: extending optimizable k-dissimilarity selection to combinatorial library design

Optimizable k-dissimilarity (OptiSim) selection entails drawing a series of subsamples of size k from a population and choosing the "best" candidate from each such subsample for inclusion in the selection set. By varying the size of the subsample, one can control the balance between representativeness and diversity in the selection set obtained. In the original formulation, a uniform random sampling from among valid candidates was used to draw the subsamples from a single target population. Here we describe in detail two key modifications that serve to extend the OptiSim methodology to vector selection for interdependent variables, specifically as applied to the design of combinatorial sublibraries. The first modification involves pivoting between variables: subsamples are drawn from each reagent pool in turn, with the viability of each candidate being evaluated in isolation as well as in terms of the products it will produce from complementary reagents already selected. The filters applied may be static or dynamic in nature, with molecular weight and hydrophobicity being examples of the former and structural diversity with respect to reagents already selected being an example of the latter. The second key modification is adding the ability to bias the selection of candidate reagents for inclusion in the subsamples. Taken together, these modifications support the efficient generation of multiblock and other sparse matrix designs that are both representative and diverse, and for which "backfilling" of designs edited to remove undesirable reagents or products is straightforward. The method is intrinsically fast and efficient, since enumeration of the full combinatorial is not required- only those candidates actually considered for inclusion need be evaluated. Moreover, because the subsample selection step is separate from the diversity-based selection of the "best" candidate, incorporating such bias in favor of a competing criterion such as low price provides a "natural," nonparametric mechanism for generating designs that are likely to be "good" in a double-objective, Pareto sense.     

A consecutive Diels-Alder approach toward a Tet repressor directed combinatorial library

A combinatorial library of 180 tetracycline analogs was generated by solution phase parallel synthesis applying a consecutive Diels-Alder strategy. Chemical methodology suitable for three-dimensional solution phase parallel synthesis was developed that enabled us to generate a collection of potential TetR inducers. The synthesis was built on cross-conjugated trienes as central building blocks facilitating two consecutive cycloaddition processes with different dienophiles. Upon sequential exposure to naphthoquinone and maleimide derivatives, the generation of a carbocyclic skeleton of type 2 incorporating the diversity elements R¹-R⁵ was envisaged.     

CombiDOCK: Structure-based combinatorial docking and library design

We have developed a strategy for efficiently docking a large combinatorial library into a target receptor. For each scaffold orientation, all potential fragments are attached to the scaffold, their interactions with the receptor are individually scored and factorial combinations of fragments are constructed. To test its effectiveness, this approach is compared to two simple control algorithms. Our method is more efficient than the controls at selecting best scoring molecules and at selecting fragments for the construction of an exhaustive combinatorial library. We also carried out a retrospective analysis of the experimental results of a 10×10×10 exhaustive combinatorial library. An enrichment factor of approximately 4 was found for identifying the compounds in the library that are active at 330 nM.     

Rational principles of compound selection for combinatorial library design

It is practically impossible in a short period of time to synthesize and test all compounds in any large exhaustive chemical library. We discuss rational approaches to selecting representative subsets of virtual libraries that help direct experimental synthetic efforts for both targeted and diverse library design. For targeted library design, we consider principles based on the similarity to lead molecules. In the case of diverse library design, we discuss algorithms aimed at the selection of both diverse and representative subsets of the entire chemical library space. We illustrate methodologies with several practical examples.     

Computational methods and software in computer-aided combinatorial library design

Recent trends in the computer-aided design of diverse and focussed combinatorial libraries are surveyed. First, chemical data input, storage and retrieval including chemical database management and virtual chemical structure enumeration are outlined as background. Then, the optimization of ADMET parameters, diversity maximization, molecular similarity search, QSAR-based virtual screening, pharmacophore search and molecular docking are discussed.     

GLARE: a new approach for filtering large reagent lists in combinatorial library design using product properties

We present a novel computer algorithm, called GLARE (Global Library Assessment of REagents), that addresses the issue of optimal reagent selection in combinatorial library design. This program reduces or eliminates the time a medicinal chemist spends examining reagents which a priori cannot be part of a "good" library. Our approach takes the large reagent sets returned by standard chemical database queries and produces often considerably reduced reagent sets that are well-behaved with respect to a specific template. The pruning enforces "goodness" constraints such as the Lipinski rule of five on the product properties such that any reagent selection from the resulting sets produces only "good" products. The algorithm we implemented has three important features: (i) As opposed to genetic algorithms or other stochastic algorithms, GLARE uses a deterministic greedy procedure that smoothly filters out nonviable reagents. (ii) The pruning method can be biased to produce reagent sets with a balanced size, conserving proportionally more reagents in smaller sets. (iii) For very large combinatorial libraries, a partitioning scheme allows libraries as large as 10(12) to be evaluated in 0.25 s on an IBM AMD Opteron processor. This algorithm is validated on a diverse set of 12 libraries. The results that we obtained show an excellent compliance to the product property requirements and very fast timings.     

Discovery of a novel synthetic phosphatase from a bead-bound combinatorial library

Using split/pool encoded synthesis and a colorimetric catalysis assay, a number of synthetic phosphatase catalysts were developed.     

Scaffold diversity of natural products: inspiration for combinatorial library design

Natural products contain scaffold structures that can be systematically exploited for the design of combinatorial compound libraries with druglike properties. We review approaches for scaffold identification, and compare properties and pharmacophoric features of drugs and natural products. In particular, an application of the self-organizing map technique is presented for natural product-derived compound and library design.     

A combinatorial approach to branched polymers’ statistics

At least ideally, a certain class of polymers presents itself as a collection (set) of connected components. Each of these components is a cycle of trees, that is branched polymers eventually rooted on a cycle. We derive (and study) an equilibrium statistical model that accounts for the main connectivity features of such structures, whose origin is to be found in combinatorial probability. Phase transition (gel–soltransition) is shown to occur when some internal control parameter crosses one (critical parameter). Various structural asymptotic results are shown to be available using singularity analysis. This revised version was published online in July 2006 with corrections to the Cover Date.     

A combinatorial approach to the electron correlation problem

Starting from a path-integral formulation of quantum statistical mechanics expressed in a space of Slater determinants, we develop a method for the Monte Carlo evaluation of the energy of a correlated electronic system. The path-integral expression for the partition function is written as a contracted sum over graphs. A graph is a set of distinct connected determinants on which paths can be represented. The weight of a graph is given by the sum over exponentially large numbers of paths which visit the vertices of the graph. We show that these weights are analytically computable using combinatorial techniques, and they turn out to be sufficiently well behaved to allow stable Monte Carlo simulations in which graphs are stochastically sampled according to a Metropolis algorithm. In the present formulation, graphs of up to four vertices have been included. In a Hartree-Fock basis, this allows for paths which include up to sixfold excitations relative to the Hartree-Fock determinant. As an illustration, we have studied the dissociation curve of the N(2) molecule in a VDZ basis, which allows comparison with full configuration-interaction calculations.     

A novel design approach for lithium-sulphur batteries

A novel microwave synthesis path for sulphur-carbon compounds for lithium batteries was successfully developed. Model electrodes built from these materials showed an excellent and highly stable electrochemical performance over several hundred of cycles with a remarkable initial specific charge of about 1300 A h kg^?1 and a remaining specific charge of 1012 A h kg^?1 (at 1 C) after about 500 cycles. In addition, a silicon-containing anode setup was used to investigate the highly beneficial influence of silicon nanowires on the electrochemical properties of lithium-sulphur batteries.     

Rapid identification of substrates for novel proteases using a combinatorial peptide library

Fluorogenic substrates for assaying novel proteolytic enzymes could be rapidly identified using an easy, solid-phase combinatorial assay technology. The methodology was validated with leader peptidase of Escherichia coli using a subset of an intramolecularly quenched fluorogenic peptide library. The technique was extended toward the discovery of substrates for a new aspartic protease of pharmaceutical relevance (human napsin A). We demonstrated for the first time known to us that potent fluorogenic substrates can be discovered using extracts of cells expressing recombinant enzyme to screen the peptide library. The straightforward and rapid optimization of protease substrates greatly facilitates the drug discovery process by speeding up the development of high throughput screening assays and thus helps more effective exploitation of the enormous body of information and chemical structures emerging from genomics and combinatorial chemistry technologies.     

Application of self-organizing maps in compounds pattern recognition and combinatorial library design

In the computer-aided drug design, in order to find some new leads from a large library of compounds, the pattern recognition study of the diversity and similarity assessment of the chemical compounds is required; meanwhile in the combinatorial library design, more attention is given to design target focusing library along with diversity and drug-likeness criteria. This review presents the current state-of-art applications of Kohonen self-organizing maps (SOM) for studying the compounds pattern recognition, comparing the property of molecular surfaces, distinguishing drug-like and nondrug-like molecules, splitting a dataset into the proper training and test sets before constructing a QSAR (Quantitative Structural-Activity Relationship) model, and also for the combinatorial libraries comparison and the combinatorial library design. The Kohonen self-organizing map will continue to play an important role in drug discovery and library design.     

Facile acetal dynamic combinatorial library

We herein report our first results on the use of simple acetalation chemistry in the service of dynamic combinatorial libraries (DCLs); the reaction between triethylene glycol and 4-nitrobenzaldehyde afforded a DCL of more than 15 cyclic and acyclic species; all of which were separated and characterized; the smaller macrocyclic compounds were successfully amplified by the use of ammonium ions.