title: Insight into the structural requirements of aminopyrimidine derivatives for good potency against both purified enzyme and whole cells of M. tuberculosis: combination of HQSAR, CoMSIA, and MD simulation studies.
abstract: The Mycobacterium tuberculosis protein kinase B (PknB) is critical for growth and survival of M. tuberculosis within the host. The series of aminopyrimidine derivatives show impressive activity against PknB (IC50 < .5 μM). However, most of them show weak or no cellular activity against M. tuberculosis (MIC > 63 μM). Consequently, the key structural features related to activity against of both PknB and M. tuberculosis need to be investigated. Here, two- and three-dimensional quantitative structure-activity relationship (2D and 3D QSAR) analyses combined with molecular dynamics (MD) simulations were employed with the aim to evaluate these key structural features of aminopyrimidine derivatives. Hologram quantitative structure-activity relationship (HQSAR) and CoMSIA models constructed from IC50 and MIC values of aminopyrimidine compounds could establish the structural requirements for better activity against of both PknB and M. tuberculosis. The NH linker and the R1 substituent of the template compound are not only crucial for the biological activity against PknB but also for the biological activity against M. tuberculosis. Moreover, the results obtained from MD simulations show that these moieties are the key fragments for binding of aminopyrimidine compounds in PknB. The combination of QSAR analysis and MD simulations helps us to provide a structural concept that could guide future design of PknB inhibitors with improved potency against both the purified enzyme and whole M. tuberculosis cells.
authors.affiliation: a Faculty of Science , Nakhon Phanom University , Nakhon Phanom , Thailand.
authors.forename: Auradee
authors.initials: A
authors.lastname: Punkvang
authors.affiliation: b Department of Chemistry , Kasetsart University , Bangkok , Thailand.
authors.forename: Supa
authors.initials: S
authors.lastname: Hannongbua
authors.affiliation: b Department of Chemistry , Kasetsart University , Bangkok , Thailand.
authors.forename: Patchreenart
authors.initials: P
authors.lastname: Saparpakorn
authors.affiliation: c Department of Chemistry , Ubon Ratchathani University , Ubonratchathani , Thailand.
authors.forename: Pornpan
authors.initials: P
authors.lastname: Pungpo
mesh_terms: D019943:Amino Acid Substitution; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D039301:Computers, Molecular; D055808:Drug Discovery; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D011743:Pyrimidines; C012180:2-aminopyrimidine
keywords: M. tuberculosis; MD simulation; PknB; QSAR; tuberculosis