A combination of docking and cheminformatics approaches for the identification of inhibitors against 4′ phosphopantetheinyl transferase of

• Published in: RSC advances 2018-01, Vol.8 (1), p.328-341
• Main Authors: Rohilla, Akshay, Khare, Garima, Tyagi, Anil K
• Format: Article
• ISSN: 2046-2069
• DOI: 10.1039/c7ra11198c

4′ Phosphopantetheinyl transferase (PptT) is involved in post translational modification by carrying out phosphopantetheinylation of proteins in non-ribosomal peptide synthesis and polyketide synthesis pathways of various organisms. PptT was recently shown to be crucial for the survival as well as persistence of Mycobacterium tuberculosis ( M. tb ) in mice models thus demonstrating it to be an attractive drug target. By employing Autodock 4.2 and Glide, we virtually screened the filtered NCI library against the active site of PptT and out of the 205 molecules tested in vitro , 13 molecules exhibited potent enzyme inhibition with IC 50 ≤ 10 μg ml −1 . Further evaluation of the molecules against the in vitro growth of M. tb resulted in the identification of six compounds that exhibited inhibition of both enzyme activity as well as M. tb growth. Subsequently, a cheminformatics based structure similarity approach led to the identification of 5 analogues of P-52 (IC 50 - 2.25 μg ml −1 and MIC 90 - 77.5 μg ml −1 ) with IC 50 ≤ 1 μg ml −1 thereby establishing N , N -diethyl- N ′-(2-methylquinolin-8-yl)propane-1,3-diamine as one of the potent inhibitory scaffolds of PptT. The inhibitors were further evaluated for their MIC 90 values as well as cytotoxicity against various mammalian cell lines. PS-40 (NSC-328398), an analogue of P-52, emerged as a potent inhibitory molecule which exhibited an IC 50 of 0.25 μg ml −1 , MIC 90 of 10 μg ml −1 and negligible cytotoxicity with a selectivity index >10 against three mammalian cell lines tested. Thus, our study identified potent inhibitory scaffolds against 4′ phosphopantetheinyl transferase of M. tb , an important drug target of M. tb . We integrated virtual screening, in vitro and ex vivo approaches to identify numerous potent inhibitory scaffolds against M. tb PptT.