Designing active template molecules by combining computational de novo design and human chemist's expertise.

@article{Lameijer2007DesigningAT,
  title={Designing active template molecules by combining computational de novo design and human chemist's expertise.},
  author={Eric-Wubbo Lameijer and Reynier A. Tromp and Ronald F Spanjersberg and Johannes Brussee and Adriaan P. IJzerman},
  journal={Journal of medicinal chemistry},
  year={2007},
  volume={50 8},
  pages={
          1925-32
        }
}
We used a new software tool for de novo design, the "Molecule Evoluator", to generate a number of small molecules. Explicit constraints were a relatively low molecular weight and otherwise limited functionality, for example, low numbers of hydrogen bond donors and acceptors, one or two aromatic rings, and a small number of rotatable bonds. In this way, we obtained a collection of scaffold- or templatelike molecules rather than fully "decorated" ones. We asked medicinal chemists to evaluate the… 

Figures and Tables from this paper

Predicting the synthetic accessibility of drug-like molecules

TLDR
Here, a synthetic accessibility score for the Molecule Evoluator Tool is developed that incorporates the molecular complexity of a molecule, as well as the number of stereocenters and the similarity to available starting materials.

De novo drug design.

TLDR
State-of-the-art software for de novo drug design with a special emphasis on fragment-based techniques that generate druglike, synthetically accessible compounds are reviewed, and the importance of scoring functions that can be used to predict compound reactivity and potency is highlighted.

Generation of New Synthetic Scaffolds Using Framework Libraries Selected and Refined via Medicinal Chemist Synthetic Expertise

TLDR
An improved stepwise general method is delineated that uses virtual framework libraries to identify frameworks that rigidly match specific aspects of a ligand's bioactive conformation.

De Novo Design at the Edge of Chaos.

TLDR
The current perspective on the concept of automated molecule generation is presented by highlighting chemocentric methods that may capture druglike chemical space, consider ligand promiscuity for hit and lead finding, and provide fresh ideas for the rational design of customized screening of compound libraries.

De novo design: balancing novelty and confined chemical space

TLDR
This article discusses recent advances in de novo drug design programs and accessory programs used to evaluate compounds post-generation and provides a means of enhancing the therapeutic value of these generated compounds.

From Molecular Shape to Potent Bioactive Agents II: Fragment‐Based de novo Design

TLDR
This study presents the successful de novo design of a PPAR agonist using a novel fragment-based compound assembly strategy and develops a software tool that generates suggestions for bioisosteric ACHTUNGTRENNUNGreplacements to be exploited by medicinal chemists for the ACHtUNgTRENNunGgeneration of novel lead structures.

Multi-Objective Evolutionary Design of Adenosine Receptor Ligands

TLDR
An increased affinity with appreciable selectivity for hA1AR over the other adenosine receptor subtypes was achieved through substitution of the scaffold; compound 3a had a Ki value of 280 nM with approximately 10-fold selectivity with respect to hA2AR, while 3g had a 1.6 μM affinity, which was guided by the substitution patterns as observed in the set of generated compounds that contained scaffold 3.

A Structure-Based Drug Discovery Paradigm

TLDR
This review focuses on the currently available methods and algorithms for structure-based drug design including virtual screening and de novo drug design, with a special emphasis on AI- and deep-learning-based methods used for drug discovery.

Chemoinformatics and Computational Chemical Biology

TLDR
A meta-informatics approach to the Rational Design of siRNA Libraries and the Interweaving of Cheminformatics and HTS, and Application of Support Vector Machine-Based Ranking Strategies to Search for Target-Selective Compounds.

References

SHOWING 1-10 OF 25 REFERENCES

De novo design of molecular architectures by evolutionary assembly of drug-derived building blocks

TLDR
The efficiency of the design algorithm was demonstrated for the de novo construction of potential thrombin inhibitors mimicking peptide and non-peptide template structures and the concept of varying library `diversity' during a design process was consequently implemented by using adaptive variant distributions.

SYNOPSIS: SYNthesize and OPtimize System in Silico.

TLDR
A de novo design program called SYNOPSIS, that includes a synthesis route for each generated molecule, which resulted in 18 synthesized and tested compounds, 10 of which showed HIV inhibitory activity in vitro.

Design of new selective inhibitors of cyclooxygenase-2 by dynamic assembly of molecular building blocks

TLDR
The results from clustering indicate that the structural motifs in the diarylheterocycle class of COX-2-selective inhibitors have been generated using the revised DycoBlock, and their binding modes were investigated.

The properties of known drugs. 1. Molecular frameworks.

TLDR
This work uses shape description methods to analyze a database of commercially available drugs and prepares a list of common drug shapes, finding that the diversity of shapes in the set of known drugs is extremely low.

A genetic algorithm for the automated generation of small organic molecules: Drug design using an evolutionary algorithm

TLDR
LEA has been designed in order to conceive novel small organic molecules which satisfy quantitative structure-activity relationship based rules (fitness), and the results may be promising for chemical synthesis and show that this tool may find extensive applications in de novo drug design projects.

Properties of known drugs. 2. Side chains.

TLDR
Using shape description methods, a database of commercially available drugs is divided into a list of common drug side chains, and it is suggested that the diversity that side chains provide to drug molecules is quite low.

Computer-based de novo design of drug-like molecules

TLDR
This review outlines the various design concepts and highlights current developments in computer-based de novo design of hit and lead structure candidates for drug discovery projects.

A genetic algorithm for structure-based de novo design

TLDR
The ADAPT program, a genetic algorithm which uses molecular interactions evaluated with docking calculations as a fitness function to reduce the search space, is developed and its application to three well-studied target systems is described.

Development of a Method for Evaluating Drug-Likeness and Ease of Synthesis Using a Data Set in Which Compounds Are Assigned Scores Based on Chemists' Intuition

TLDR
Binary classifiers with an artificial neural network and a support vector machine are devised to efficiently eliminate compounds that are not drug-like and/or hard-to-synthesize derivatives, demonstrating the suitability of these models for use as compound acquisition filters.

Assessment of the consistency of medicinal chemists in reviewing sets of compounds.

TLDR
It was found that medicinal Chemists were not very consistent in the compounds they rejected as being undesirable, which has important implications for pharmaceutical project teams where individual medicinal chemists review lists of primary screening hits to identify those compounds suitable for follow-up.