Similarity-Based Virtual Screening to Find Antituberculosis Agents Based on Novel Scaffolds: Design, Syntheses and Pharmacological Assays

• Published in: International journal of molecular sciences Vol. 23; no. 23; p. 15057
• Main Authors: García-García, Ángela, Julián-Ortiz, Jesus Vicente de, Gálvez, Jorge, Font, David, Ayats, Carles, Guna Serrano, María Del Remedio, Muñoz-Collado, Carlos, Borrás, Rafael, Villalgordo, José Manuel
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.12.2022; MDPI
• Subjects: antimicrobial drugs; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Classification; Databases, Factual; Discriminant analysis; Drug Design; Identification methods; linear discriminant analysis; Mathematical models; Molecular Structure; MTBC; pharmacological activity distribution diagrams; Probability; Pyrimidines; Quantitative Structure-Activity Relationship; Scaffolds; topological indices; virtual screening; topological indices; antimicrobial drugs; virtual screening; drug design; MTBC; linear discriminant analysis; pharmacological activity distribution diagrams
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232315057

A method to identify molecular scaffolds potentially active against the Mycobacterium tuberculosis complex (MTBC) is developed. A set of structurally heterogeneous agents against MTBC was used to obtain a mathematical model based on topological descriptors. This model was statistically validated through a Leave-n-Out test. It successfully discriminated between active or inactive compounds over 86% in database sets. It was also useful to select new potential antituberculosis compounds in external databases. The selection of new substituted pyrimidines, pyrimidones and triazolo[1,5- ]pyrimidines was particularly interesting because these structures could provide new scaffolds in this field. The seven selected candidates were synthesized and six of them showed activity in vitro.