Pierre Acklin

Comparison of fingerprint-based methods for virtual screening using multiple bioactive reference structures

Fingerprint-based similarity searching is widely used for virtual screening when only a single bioactive reference structure is available. This paper reviews three distinct ways of carrying out such searches when multiple bioactive reference structures are available: merging the individual fingerprints into a single combined fingerprint; applying data fusion to the similarity rankings resulting from individual similarity searches; and approximations to substructural analysis. Extended searches on the MDL Drug Data Report database suggest that fusing similarity scores is the most effective general approach, with the best individual results coming from the binary kernel discrimination technique.

Comparison of topological descriptors for similarity-based virtual screening using multiple bioactive reference structures

This paper reports a detailed comparison of a range of different types of 2D fingerprints when used for similarity-based virtual screening with multiple reference structures. Experiments with the MDL Drug Data Report database demonstrate the effectiveness of fingerprints that encode circular substructure descriptors generated using the Morgan algorithm. These fingerprints are notably more effective than fingerprints based on a fragment dictionary, on hashing and on topological pharmacophores. The combination of these fingerprints with data fusion based on similarity scores provides both an effective and an efficient approach to virtual screening in lead-discovery programmes.

Development of Tridentate Iron Chelators: From Desferrithiocin to ICL670

Successful treatment of beta-thalassemia requires two key elements: blood transfusion and iron chelation. Regular blood transfusions considerably expand the lifespan of patients, however, without the removal of the consequential accumulation of body iron, few patients live beyond their second decade. In 1963, the introduction of desferrioxamine (DFO), a hexadentate chelator, marked a breakthrough in the treatment of beta-thalassemia. DFO significantly reduces body iron burden and iron-related morbidity and mortality. DFO is still the only drug for general use in the treatment of transfusion dependent iron overload. However, its very short plasma half-life and poor oral activity necessitate special modes of application (subcutaneous or intravenous infusion) which are inconvenient, can cause local reactions and are difficult to be accepted by many patients. Over the past four decades, many different laboratories have invested major efforts in the identification of orally active iron chelators from several hundreds of molecules of synthetic, microbial or plant origin. The discovery of ferrithiocin in 1980, followed by the synthesis of the tridentate chelator desferrithiocin and proof of its oral activity raised a lot of hope. However, the compound proved to be toxic in animals. Over a period of about fifteen years many desferrithiocin derivatives and molecules with broader alterations led to the discovery of numerous new compounds some of which were much better tolerated and were more efficacious than desferrithiocin in animals, however, none was safe enough to proceed to the clinical use. The discovery of a new chemical class of iron chelators: The bis-hydroxyphenyltriazoles re-energized the search for a safe tridentate chelator. The basic structure of this completely new chemical class of iron chelators was discovered by a combination of rational design, intuition and experience. More than forty derivatives of the triazole series were synthesized at Novartis. These compounds were evaluated, together with more than 700 chelators from various chemical classes. Using vigorous selection criteria with a focus on tolerability, the tridentate chelator 4-[(3,5-Bis-(2-hydroxyphenyl)-1,2,4)triazol-1-yl]-benzoic acid (ICL670) emerged as an entity which best combined high oral potency and tolerability in animals. ICL670 is presently being evaluated in the clinic.

New Methods for Ligand-Based Virtual Screening: Use of Data Fusion and Machine Learning to Enhance the Effectiveness of Similarity Searching

Similarity searching using a single bioactive reference structure is a well-established technique for accessing chemical structure databases. This paper describes two extensions of the basic approach. First, we discuss the use of group fusion to combine the results of similarity searches when multiple reference structures are available. We demonstrate that this technique is notably more effective than conventional similarity searching in scaffold-hopping searches for structurally diverse sets of active molecules; conversely, the technique will do little to improve the search performance if the actives are structurally homogeneous. Second, we make the assumption that the nearest neighbors resulting from a similarity search, using a single bioactive reference structure, are also active and use this assumption to implement approximate forms of group fusion, substructural analysis, and binary kernel discrimination. This approach, called turbo similarity searching, is notably more effective than conventional similarity searching.

4‐[3,5‐Bis(2‐hydroxyphenyl)‐1,2,4‐triazol‐1‐yl]‐ benzoic Acid: A Novel Efficient and Selective Iron(III) Complexing Agent

An exceptionally stable 1:2 complex [FeL2]3− is formed from the ligand H3L and FeIII. In contrast, the affinity of this ligand for other biometals is relatively small. These properties make H3L a highly promising candidate for medical applications (e.g. for the treatment of iron overload).

Key aspects of the Novartis compound collection enhancement project for the compilation of a comprehensive chemogenomics drug discovery screening collection.

The NIBR (Novartis Institutes for BioMedical Research) compound collection enrichment and enhancement project integrates corporate internal combinatorial compound synthesis and external compound acquisition activities in order to build up a comprehensive screening collection for a modern drug discovery organization. The main purpose of the screening collection is to supply the Novartis drug discovery pipeline with hit-to-lead compounds for todays and the futures portfolio of drug discovery programs, and to provide tool compounds for the chemogenomics investigation of novel biological pathways and circuits. As such, it integrates designed focused and diversity-based compound sets from the synthetic and natural paradigms able to cope with druggable and currently deemed undruggable targets and molecular interaction modes. Herein, we will summarize together with new trends published in the literature, scientific challenges faced and key approaches taken at NIBR to match the chemical and biological spaces.

ICL670A: Preclinical Profile

Man is unable to actively eliminate iron from the body, once it has been acquired. Toxic and eventually lethal levels of iron accumulate as a result of repeated transfusions, e.g. in s-thalassemia major, or due to excessive dietary iron uptake in anemias and hereditary hemochromatosis. Excess iron is deposited in the form of hemosiderins (insoluble “iron cores” of ferritin) mainly in the liver, spleen, many endocrine organs and in the myocardium. The exact mechanism of iron damage to these tissues is unknown, but it is established that organ failure correlates with iron burden in these tissues. Except for infectious diseases, cardiac complications are the major cause of death in s-thalassemia major patients.

Enrichment of Extremely Noisy High-Throughput Screening Data Using a Naïve Bayes Classifier

The noise level of a high-throughput screening (HTS) experiment depends on various factors such as the quality and robustness of the assay itself and the quality of the robotic platform. Screening of compound mixtures is noisier than screening single compounds per well. A classification model based on naïve Bayes (NB) may be used to enrich such data. The authors studied the ability of the NB classifier to prioritize noisy primary HTS data of compound mixtures (5 compounds/well) in 4 campaigns in which the percentage of noise presumed to be inactive compounds ranged between 81% and 91%. The top 10% of the compounds suggested by the classifier captured between 26% and 45% of the active compounds. These results are reasonable and useful, considering the poor quality of the training set and the short computing time that is needed to build and deploy the classifier. (Journal of Biomolecular Screening 2004:32-36)

N-Phosphonoalkyl-5-aminomethylquinoxaline-2,3-diones: In vivo active AMPA and NMDA(glycine) antagonists

N-Substituted 5-aminomethylquinoxalinediones containing carboxy or phosphonic acids yield potent and selective AMPA and/or NMDA (glycine-binding site) antagonists. Phosphonic acid derivatives are particularly water-soluble and display potent anticonvulsant effects in the electroshock-induced convulsion assay in mice.

5-Aminomethylquinoxaline-2,3-diones, Part III: Arylamide derivatives as highly potent and selective glycine-site NMDA receptor antagonists.

A series of quinoxaline-2,3-diones with very high affinity to the glycine site of the NMDA receptor has been discovered. In contrast to the 7-nitro derivatives, the most potent 7-bromo substituted compounds were highly selective for the glycine site. Although none of the described compounds were active in the electroshock model in mice, 1a displayed significant protection in the quinolinic acid-induced excitotoxicity model in vivo.