Evolutionary computation and multimodal search: A good combination to tackle molecular diversity in the field of peptide design

Summary The awesome degree of structural diversity accessible in peptide design has created a demand for computational resources that can evaluate a multitude of candidate structures. In our specific case, we translate the peptide design problem to an optimization problem, and use evolutionary computation (EC) in tandem with docking to carry out a combinatorial search. However, the use of EC in huge search spaces with different optima may pose certain drawbacks. For example, EC is prone to focus a search in the first good region found. This is a problem not only because of the undesirable and automatic rejection of potentially good search space regions, but also because the found solution may be extremely difficult to synthesize chemically or may even be a false docking positive. In order to avoid rejecting potentially good solutions and to maximize the molecular diversity of the search, we have implemented evolutionary multimodal search techniques, as well as the molecular diversity metric needed by the multimodal algorithms to measure differences between various regions of the search space.     

Cheminformatic characterization of natural products from Panama

In this work, we discuss the characterization and diversity analysis of 354 natural products (NPs) from Panama, systematically analyzed for the first time. The in-house database was compared to NPs from Brazil, compounds from Traditional Chinese Medicine, natural and semisynthetic collections used in high-throughput screening, and compounds from ChEMBL. An analysis of the “global diversity” was conducted using molecular properties of pharmaceutical interest, three molecular fingerprints of different design, molecular scaffolds, and molecular complexity. The global diversity was visualized using consensus diversity plots that revealed that the secondary metabolites in the Panamanian flora have a large scaffold diversity as compared to other composite databases and also have several unique scaffolds. The large scaffold diversity is in agreement with the broad range of biological activities that this collection of NPs from Panama has shown. This study also provided further quantitative evidence of the large structural complexity of NPs. The results obtained in this study support that NPs from Panama are promising candidates to identify selective molecules and are suitable sources of compounds for virtual screening campaigns.     

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.     

Chemoinformatics methods for systematic comparison of molecules from natural and synthetic sources and design of hybrid libraries

Until recently, the field of diversity and library design has more or less ignored naturalproducts as a compound source. This is probably due to at least two reasons. First,combinatorial and reaction-based approaches have been major focal points in the earlydays of computational library design. In addition, a widespread view is that naturalproducts are often highly complex and not amenable to medicinal chemistry efforts. Thiscontribution introduces recent computational approaches to systematically analyzenatural molecules and bridge the gap between natural products and synthetic chemistryprograms. Large scale comparisons of natural and synthetic molecules are discussed aswell as studies designed to identify `synthetic mimics' of natural products with specificactivity. In addition, a concept for the design of natural/synthetic hybrid libraries isintroduced. Although research in this area is still in its early stages, an important lesson tobe learned from computational analyses is that there is no need to a priori `shy away'from natural products as a source for molecular design.     

Comparative molecular surface analysis: A novel tool for drug design and molecular diversity studies

The application of the SOM network in drug design and molecular diversity is discussed. In particular, examples of the applications of the Comparative Molecular Surface Analysis (CoMSA) are reviewed. Molecular surface is a fuzzy category, inspired by the macroscopic world, which has no unique equivalent in the molecular scale. However, it is somewhere near the area where the molecular recognition processes are taking place. Consequently, the methods that analyze this region promise better efficiency than procedures that are based on uniform grids. An important advantage of the CoMSA method is the possibility for the generation of fuzzy molecular representations together with its ability to discover such aspects of molecular similarity that can be easily overlooked by a chemist. The ability for data compression is a further advantage. It has also been shown that the fast processing of the comparative Kohonen mapping enables one to implement this method in the field of molecular diversity.     

Design considerations and computer modeling related to the development of molecular scaffolds and peptide mimetics for combinatorial chemistry

Summary A critical issue in drug discovery utilizing combinatorial chemistry as part of the discovery process is the choice of scaffolds to be used for a proper presentation, in a three-dimensional space, of the critical elements of structure necessary for molecular recognition (binding) and information transfer (agonist/ antagonist). In the case of polypeptide ligands, considerations related to the properties of various backbone structures (-helix, -sheets, etc.; , space) and those related to three-dimensional presentation of side-chain moieties (topography; (chi) space) must be addressed, although they often present quite different elements in the molecular recognition puzzle. We have addressed aspects of this problem by examining the three-dimensional structures of chemically different scaffolds at various distances from the scaffold to evaluate their putative diversity. We find that chemically diverse scaffolds can readily become topographically similar. We suggest a topographical approach involving design in chi space to deal with these problems.     

Design and analysis of the four-mirror optical system

Based on the methods to design the three-mirror reflective system, the aberrations formulae for the four-mirror optical reflection system have been deduced and presented for the first time. The diversity of parameter ranges for the designed system for different structures is also studied to select the parameters to obtain the practicable initial structure. Example designs with proposed methods are presented here and their performance evaluations demonstrate that the image qualities of these examples attain the diffraction limits.     

Diversity management for efficient combinatorial optimization of materials

We describe the issues of evolutionary library design in the frame of Material and Catalyst discovery. Concepts of diversity management on material library to enhance the efficiency of the optimization are proposed. The diversity monitoring is implemented by two different approaches. The first deals with a dynamic monitoring of mutation and crossover rates whereas the second involves a selection step based on sample “distance”. Simulations of optimization are performed on a surface response which is designed to mimic realistic data. Algorithm performances are compared in terms of both efficiency and reliability.     

Alchemical molecular dynamics for inverse design

We present a molecular dynamics (MD) implementation of an extended statistical mechanical ensemble that includes ‘alchemical’ degrees of freedom describing particle attributes as thermodynamic variables. We demonstrate the use of this alchemical MD method in inverse design simulations of particles interacting via the Oscillating Pair Potential (OPP) and the Lennard–Jones–Gauss potential (LJG) – two general, previously studied models for which phase diagrams are known. We show that alchemical MD can quickly and efficiently optimise pair potentials for target structures within a specified design space in the low-temperature regime, where internal energy adequately represents the features of the alchemical free energy landscape. We show that alchemical MD can be also used to inversely design pair potentials to achieve target materials properties (here, bulk modulus) directly, without explicit knowledge of the structure–property relationship. Alchemical MD can easily be generalised and applied to any target materials properties or structures and used with any differentiable interaction potential.     

Software package for designing/planning fiber networks in the subscriber loop

A software package is described that was developed to assist in the processes of design and planning associated with the deployment of optical fiber in the subscriber loop (or access network). The software implementation provides a novel solution for deriving spectral forward and return losses from a diversity of routes in an optical network through the application of object-oriented technology. This technique represents a comprehensive treatment that is not based on a single-path, which enables a wide range of optical network designs to be rapidly created and subsequently characterized directly on actual geographical sites.     

Statistical molecular design of peptoid libraries

Statistical experimental design provides an efficient approach for selecting the building blocks to span the structural space and increase the information content in a combinatorial library. A set of renin-inhibitors, hexapeptoids, is used to illustrate the approach. Multivariate quantitative structure-activity relationships (MQSARs) were developed relating renin inhibition to the peptoid sequences variation, parametrized by the z-scales. By using the information from the models, the number of building block sets could be reduced from six to three. Using a statistical molecular design (SMD) reduces the number of compounds from more than 100 000 down to 90. A second SMD was used for comparison, based on less prior knowledge. This gave a reduction from over 2 billion to 120 compounds.     

Focused enumeration and assessing the structural diversity of scaffold libraries: conformationally restricted bicyclic secondary diamines

Comprehensive enumeration of conformationally restricted bicyclic secondary diamines (CRDA) was performed within defined structural limits, yielding a library of all theoretically possible compounds of this class, potentially useful as building blocks for drug design. In order to assess structural diversity of the generated library, molecular geometries of the library members were optimized using DFT calculations. It was shown that the distance between the amino groups and their relative orientation in space vary widely over the whole library, which might be beneficial for diversity-oriented conformational restriction approach in drug discovery. There are many representatives of "three-dimensional" scaffolds in the CRDA library. Selected literature data on biological activity of the known CRDA derivatives were discussed, demonstrating utility of the CRDA scaffold hopping in drug design.     

Chemoinformatics methods for systematic comparison of molecules from natural and synthetic sources and design of hybrid libraries

Until recently, the field of diversity and library design has more or less ignored natural products as a compound source. This is probably due to at least two reasons. First, combinatorial and reaction-based approaches have been major focal points in the early days of computational library design. In addition, a widespread view is that natural products are often highly complex and not amenable to medicinal chemistry efforts. This contribution introduces recent computational approaches to systematically analyze natural molecules and bridge the gap between natural products and synthetic chemistry programs. Large scale comparisons of natural and synthetic molecules are discussed as well as studies designed to identify 'synthetic mimics' of natural products with specific activity. In addition, a concept for the design of natural/synthetic hybrid libraries is introduced. Although research in this area is still in its early stages, an important lesson to be learned from computational analyses is that there is no need to a priori 'shy away' from natural products as a source for molecular design.     

Fragment-based QSAR: perspectives in drug design

Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. Quantitative structure–activity relationship (QSAR) methods are among the most important strategies that can be applied for the successful design of small molecule modulators having clinical utility. Hologram QSAR (HQSAR) is a modern 2D fragment-based QSAR method that employs specialized molecular fingerprints. HQSAR can be applied to large data sets of compounds, as well as traditional-size sets, being a versatile tool in drug design. The HQSAR approach has evolved from a classical use in the generation of standard QSAR models for data correlation and prediction into advanced drug design tools for virtual screening and pharmacokinetic property prediction. This paper provides a brief perspective on the evolution and current status of HQSAR, highlighting present challenges and new opportunities in drug design.     

What can a chemist learn from nature’s macrocycles? – A brief, conceptual view

Macrocyclic natural products often display remarkable biological activities, and many of these compounds (or their derivatives) are used as drugs. The chemical diversity of these compounds is immense and may provide inspiration for innovative drug design. Therefore, a database of naturally occurring macrocycles was analyzed for ring size, molecular weight distribution, and the frequency of some common substructural motifs. The underlying principles of the chemical diversity are reviewed in terms of biosynthetic origin and natures strategies for diversity and complexity generation in relation to the structural diversity and similarities found in the macrocycle database. Finally, it is suggested that synthetic chemists should use not only natures molecules, but also natures strategies as a source of inspiration. To illustrate this, the biosynthesis of macrocycles by non-ribosomal peptide synthetases and terpene and polyketide cyclases, as well as recent advances of these strategies in an integrated synthesis/biotechnology approach are briefly reviewed.     

有机大分子三阶非线性光学材料的研究进展

根据分子结构特征评述了各类有机大分子三阶非线性光学材料结构与性能的关系。概述了三阶非线性光学性能的计算。分析了材料分子设计原理和展望了应用前景。     

Molecular diversification in spider venoms: A web of combinatorial peptide libraries

Summary Spider venoms are a rich source of novel pharmacologically and agrochemically interesting compounds that have received increased attention from pharmacologists and biochemists in recent years. The application of technologies derived from genomics and proteomics have led to the discovery of the enormous molecular diversity of those venoms, which consist mainly of peptides and proteins. The molecular diversity of spider peptides has been revealed by mass spectrometry and appears to be based on a limited set of structural scaffolds. Genetic analysis has led to a further understanding of the molecular evolution mechanisms presiding over the generation of these combinatorial peptide libraries. Gene duplication and focal hypermutation, which has been described in cone snails, appear to be common mechanisms to venomous mollusks and spiders. Post-translational modifications, fine structural variations and new molecular scaffolds are other potential mechanisms of toxin diversification, leading to the pharmacologically complex cocktails used for predation and defense.     

从显微镜看现代仪器的设计新理念

从现代显微镜这一典型光学仪器出发,分析和阐述了现代仪器的设计新理念。提出了整体式设计、自由曲面式造型设计、人性化设计、绿色设计以及模块化设计等设计新理念。根据显微镜的发展趋势,对现代仪器的发展方向和趋势作了一个预测。