Desirability-based simultaneous analysis of binding and relative efficacy profiles of A3 adenosine receptor agonists

• Type: Article in International Scientific Journal
• Date: 2010

Authors

Maykel Cruz-Monteagudo (Author) Other; M. Natália D. S. Cordeiro (Author) FCUP; Marta Teijeira (Author) Other; Maykel Pérez González (Author) Other; Fernanda Borges (Author) FCUP

Journal

Title: Purinergic Signalling

Vol. 6 No. 1

Pages: 72-73

ISSN: 1573-9538

Publisher: Springer Nature

Indexing

ISI Web of Science

Scientific classification

FOS: Engineering and technology > Chemical engineering

CORDIS: Physical sciences > Chemistry > Applied chemistry ; Physical sciences > Chemistry > Structural chemistry

Other information

Abstract (EN): Drug discovery is inherently a multi-objective problem in which the modeling of decision preferences and constraints and the visualization and assessment of the trade-offs among objectives is yet a great challenge. As the desirability theory is a well-known multicriteria decision-making approach, it has been decided to apply it, instead for multi-objective optimization [1], to the rational design and development of adenosine agonist ligands, specifically as a prediction model tool to extract useful information on the desired trade-offs between binding and relative efficacy of A3 adenosine receptor agonists (N6-substituted-4′-thioadenosine type). The development of a linear prediction model of the A3 agonists overall desirability, as well as the desirability analysis of this model, leads to discover significant clues based on simple molecular descriptors with a direct physicochemical or structural explanation. The information retrieved guides to the design of new candidates with simultaneously improved binding and relative efficacy profiles. In particular, the model suggests a relevant role of the presence of cyclic substituents on the N6 position of the adenine ring that in turn contributes to reduce the flexibility and hydrophobicity of the molecules. Although based on a simple 1D model, the data obtained correlate well with the results previously reported with more sophisticated approaches such as 3D-COMFA [2]. In addition, the model offers other benefits: the simultaneous analysis of both binding and relative efficacy profiles of A3 agonists as well as the design of highly potent and selective agonists based on a particular and unusual structural modification. In summary, it was demonstrated that desirability theory could be a valuable tool in medicinal chemistry, namely in the development of novel and potent A3 agonist candidates.

Language: English

Type (Professor's evaluation): Scientific

Notes: in Third joint Italian-German Purine Club meeting: “Purinergic receptors: new frontiers for novel therapies”