TY - JOUR
T1 - DprE1 Inhibitors
T2 - Enduring Aspirations for Future Antituberculosis Drug Discovery
AU - Yadav, Saloni
AU - Soni, Aastha
AU - Tanwar, Omprakash
AU - Bhadane, Rajendra
AU - Besra, Gurdyal S
AU - Kawathekar, Neha
N1 - © 2023 Wiley-VCH GmbH.
PY - 2023/8/15
Y1 - 2023/8/15
N2 - DprE1 is a crucial enzyme involved in the cell wall synthesis of Mycobacterium tuberculosis and a promising target for antituberculosis drug development. However, its unique structural characteristics for ligand binding and association with DprE2 make developing new clinical compounds challenging. This review provides an in-depth analysis of the structural requirements for both covalent and non-covalent inhibitors, their 2D and 3D binding patterns, as well as their biological activity data in vitro and in vivo, including pharmacokinetic information. We also introduce a protein quality score (PQS) and an active-site map of the DprE1 enzyme to help medicinal chemists better understand DprE1 inhibition and develop new and effective anti-TB drugs. Furthermore, we examine the resistance mechanisms associated with DprE1 inhibitors to understand future developments due to resistance emergence. This comprehensive review offers insight into the DprE1 active site, including protein-binding maps, PQS, and graphical representations of known inhibitors, making it a valuable resource for medicinal chemists working on future antitubercular compounds.
AB - DprE1 is a crucial enzyme involved in the cell wall synthesis of Mycobacterium tuberculosis and a promising target for antituberculosis drug development. However, its unique structural characteristics for ligand binding and association with DprE2 make developing new clinical compounds challenging. This review provides an in-depth analysis of the structural requirements for both covalent and non-covalent inhibitors, their 2D and 3D binding patterns, as well as their biological activity data in vitro and in vivo, including pharmacokinetic information. We also introduce a protein quality score (PQS) and an active-site map of the DprE1 enzyme to help medicinal chemists better understand DprE1 inhibition and develop new and effective anti-TB drugs. Furthermore, we examine the resistance mechanisms associated with DprE1 inhibitors to understand future developments due to resistance emergence. This comprehensive review offers insight into the DprE1 active site, including protein-binding maps, PQS, and graphical representations of known inhibitors, making it a valuable resource for medicinal chemists working on future antitubercular compounds.
KW - DprE1
KW - Mycobacterium tuberculosis
KW - DprE2
U2 - 10.1002/cmdc.202300099
DO - 10.1002/cmdc.202300099
M3 - Review Article or Literature Review
C2 - 37246503
SN - 1860-7179
VL - 18
JO - ChemMedChem
JF - ChemMedChem
IS - 16
M1 - e202300099
ER -