Interactome analysis and design of inhibitors against selected protein targets of Ser/Thr protein kinase (STPK) signaling pathways in Mycobacterium tuberculosis H37Rv

Abstract

ABSTRACT. Tuberculosis continues to be a major cause of mortality worldwide despite significant advances in chemotherapy and development of the BCG vaccine. Although curable, the tuberculosis treatment period (6-9 months) presents many concerns, including patient noncompliance and the development of drug toxicity and drug resistance. This study aimed to understand the protein-protein interactions of key proteins involved in the Mycobacterium tuberculosis STPK signal transduction pathway (such as PknB, PknE, and PstP); in addition, we attempted to identify promising leads for the inhibition of protein-protein interactions. Interactome analyses revealed the interactions of these protein targets with several other proteins, including PknG and PbpA. Drug-like candidates were screened based on Lipinski's rule of five and the absorption digestion metabolism (2015) excretion toxicity. Molecular docking of the target proteins with the selected ligands identified cryptolepine HCl to be a common molecule interacting with all protein targets (with a good docking score). The generation of a pharmacophore model for cryptolepine HCl revealed three pharmacophoric regions: aromatic hydrocarbon, hydrogen bond acceptor, and hydrogen bond donor, which play important roles in its interaction with the protein targets. Therefore, cryptolepine HCl appears to be a promising drug candidate for further optimization and validation against M. tuberculosis.

Multifaced pknE: Apoptosis Inhibition, HIV Co-Infection, Host Signaling Cross-Talk and in Orchestrating the Physiology of Mycobacterium tuberculosis

“…Functional attributes of PknE substrates were already depicted with a working model in earlier report [36]. It is noteworthy that the substrates PstP and Wag31 identified as substrates for PknE by us using in vivo proteomic approach was predicted as probable substrate in a in silico based study [35].…”

“…Substrates with higher scores are depicted in Figure 1. Besides, the approaches used by us, homologous protein mapping model that encompasses data from experimentally validated substrates and STRING database suggested substrates for pknE [34,35]. However, these in silico predictions await experimental validation.…”

Structural Simplification of Cryptolepine to Obtain Novel Antifungal Quinoline Derivatives against Phytopathogenic Fungi

“…The alkaloid cryptolepine, isolated from the dried roots of Cryptolepis sanguinolenta, has attracted much attention as its multiple biological activities, such as antimicrobic, − antidiabetic, − and anti-inflammatory activity . Our previous work first reported that cryptolepine and its derivative L-03 exhibited good fungicidal activity against B.…”