title: In silico approaches and chemical space of anti-P-type ATPase compounds for discovering new antituberculous drugs.
abstract: Tuberculosis (TB) is one of the most important public health problems around the world. The emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains has driven the finding of alternative anti-TB targets. In this context, P-type ATPases are interesting therapeutic targets due to their key role in ion homeostasis across the plasma membrane and the mycobacterial survival inside macrophages. In this review, in silico and experimental strategies used for the rational design of new anti-TB drugs are presented; in addition, the chemical space distribution based on the structure and molecular properties of compounds with anti-TB and anti-P-type ATPase activity is discussed. The chemical space distribution compared to public compound libraries demonstrates that natural product libraries are a source of novel chemical scaffolds with potential anti-P-type ATPase activity. Furthermore, compounds that experimentally display anti-P-type ATPase activity belong to a chemical space of molecular properties comparable to that occupied by those approved for oral use, suggesting that these kinds of molecules have a good pharmacokinetic profile (drug-like) for evaluation as potential anti-TB drugs.
authors.affiliation: Chemistry Department, Faculty of Sciences, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Paola
authors.initials: P
authors.lastname: Santos
authors.affiliation: Chemistry Department, Faculty of Sciences, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Fabian
authors.identifier: 0000-0002-5802-9530
authors.initials: F
authors.lastname: López-Vallejo
authors.affiliation: Chemistry Department, Faculty of Sciences, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Carlos-Y
authors.initials: CY
authors.lastname: Soto
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D017076:Computer-Aided Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D006180:Proton-Translocating ATPases
keywords: 
  Mycobacterium tuberculosis
  ; P-type ATPases; antituberculous targets; chemical space; plasma membrane