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.

NU-6027 Inhibits Growth of Mycobacterium tuberculosis by Targeting Protein Kinase D and Protein Kinase G

“…Intriguingly, the lead compound failed to inhibit autophosphorylation activity associated with other STPKs, including PknA and PknB. Previously, structures with amino-pyrimidine scaffolds have been reported as inhibitors of PknB in addition to human kinase (54,55). To understand the specificity of NU-6027, detailed computational structural as well as sequence analyses were performed next.…”

Comparative analysis of PknB inhibitors for reactivity and toxicity

“…Although modifications may reduce this compound's reactivity and toxicity, further evidence is needed to assess whether it will retain its effectiveness against Mycobacterium tuberculosis. Although YH-8 is reactive and has poor pharmacokinetic properties, several stable non-reactive inhibitors are known for PknB and other related bacterial kinases, including some which were in human trials for other diseases [15][16][17][29][30][31][32][33]. Improving YH-8 by reducing its reactivity and toxicity and incorporating structure-activity relationship data from the aforementioned inhibitors may lead to improvements in the properties of YH-8, leading to a viable clinical lead compound.…”

In Silico Strategies in Tuberculosis Drug Discovery

“…Different QSAR methods have been developed and incorporated in various open-source platforms and commercial software ( Table 1). The earliest QSAR-based algorithms include Comparative Molecular Field Analyses (CoMFA) [248] and Comparative Molecular Similarity Indices Analysis (CoMSIA) [249], both of which are still widely used today for various drug discovery endeavors [250][251][252][253]. 3D-QSAR CoMFA was used by Singh and Supuran [252] for the discovery of novel Mtb carbonic anhydrase inhibitors.…”