Fragment based drug design and diversity-oriented synthesis of carboxylic acid isosteres
| Autor: | Manuel Alunno, Francesco Antonio Greco, Emidio Camaioni, Andrea Carotti, Giorgio Saluti, Roccaldo Sardella, Paride Liscio, Antonio Macchiarulo, Andrea Mammoli, Martina Ferri |
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| Rok vydání: | 2020 |
| Předmět: |
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Molecular pKa determination fragment based drug design Databases Factual Molecular model Carboxylic acid Clinical Biochemistry Carboxylic Acids Pharmaceutical Science 01 natural sciences Biochemistry Fragment (logic) Drug Discovery Molecular Biology chemistry.chemical_classification Molecular Structure 010405 organic chemistry Organic Chemistry Carboxylic acid isosteres Combinatorial chemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Drug Design Molecular Medicine Molecular modeling studies Diversity-oriented synthesis |
| Zdroj: | Bioorganic & Medicinal Chemistry. 28:115731 |
| ISSN: | 0968-0896 |
| Popis: | The medicinal chemist toolbox is plenty of (bio)isosteres when looking for a carboxylic acid replacement. However, systematic assessment of acid surrogates is often time consuming and expensive, while prediction of both physicochemical properties (logP and logD) as well as acidity would be desirable at early discovery stages for a better analog design. Herein in this work, to enable decision making on a project, we have synthesized by employing a Diversity-Oriented Synthetic (DOS) methodology, a small library of molecular fragments endowed with acidic properties. By combining in-silico and experimental methodologies these compounds were chemically characterized and, particularly, with the aim to know their physicochemical properties, the aqueous ionization constants (pKa), partition coefficients logD and logP of each fragment was firstly estimated by using molecular modeling studies and then validated by experimental determinations. A face to face comparison between data and the corresponding carboxylic acid might help medicinal chemists in finding the best replacement to be used. Finally, in the framework of Fragment Based Drug Design (FBDD) the small library of fragments obtained with our approach showed good versatility both in synthetic and physico-chemical properties. |
| Databáze: | OpenAIRE |
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