TY - JOUR
T1 - Drug repositioning for anti-tuberculosis drugs
T2 - an in silico polypharmacology approach
AU - Madugula, Sita Sirisha
AU - Nagamani, Selvaraman
AU - Jamir, Esther
AU - Priyadarsinee, Lipsa
AU - Sastry, G. Narahari
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PY - 2022/6
Y1 - 2022/6
N2 - Abstract: Development of potential antitubercular molecules is a challenging task due to the rapidly emerging drug-resistant strains of Mycobacterium tuberculosis (M.tb). Structure-based approaches hold greater benefit in identifying compounds/drugs with desired polypharmacological profiles. These methods can be employed based on the knowledge of protein binding sites to identify the complementary ligands. In this study, polypharmacology guided computational drug repurposing approach was applied to identify potential antitubercular drugs. 20 important druggable protein targets in M.tb were considered from the target library of Molecular Property Diagnostic Suite–Tuberculosis (MPDSTB–http://mpds.neist.res.in:8084) for virtual screening. FDA approved drugs were collected, preprocessed and docked in the active sites of the 20 M.tb targets. The top 300 drug molecules from each target (20 × 300) were filtered-in and subsequently screened for possible antitubercular and antimycobacterial activity using PASS tool. Using this approach, 34 drugs with predicted antitubercular and anti-mycobacterial activity were identified along with good binding affinity against multiple M.tb targets. Interestingly, 21 out of the 34 identified drugs are antibiotics while 4 drug molecules (nitrofural, stavudine, quinine and quinidine) are non-antibiotics showing promising predicted antitubercular activity. Most of these molecules have the similar privileged antimycobacterial drugs scaffold. Further drug likeness properties were calculated to get deeper insights to M.tb lead molecules. Interestingly, it was also observed that the drugs identified from the study are under different stages of drug discovery (i.e., in vitro, clinical trials) for the effective treatment of various diseases including cancer, degenerative diseases, dengue virus infection, tuberculosis, etc. Krasavin et al., 2017 synthesized nitrofuran analogues with appreciable MICs (22–23 µM) against M.tb H37Rv. These experiments further add to the credibility of the drugs identified in this study (TB). Graphic Abstract: [Figure not available: see fulltext.].
AB - Abstract: Development of potential antitubercular molecules is a challenging task due to the rapidly emerging drug-resistant strains of Mycobacterium tuberculosis (M.tb). Structure-based approaches hold greater benefit in identifying compounds/drugs with desired polypharmacological profiles. These methods can be employed based on the knowledge of protein binding sites to identify the complementary ligands. In this study, polypharmacology guided computational drug repurposing approach was applied to identify potential antitubercular drugs. 20 important druggable protein targets in M.tb were considered from the target library of Molecular Property Diagnostic Suite–Tuberculosis (MPDSTB–http://mpds.neist.res.in:8084) for virtual screening. FDA approved drugs were collected, preprocessed and docked in the active sites of the 20 M.tb targets. The top 300 drug molecules from each target (20 × 300) were filtered-in and subsequently screened for possible antitubercular and antimycobacterial activity using PASS tool. Using this approach, 34 drugs with predicted antitubercular and anti-mycobacterial activity were identified along with good binding affinity against multiple M.tb targets. Interestingly, 21 out of the 34 identified drugs are antibiotics while 4 drug molecules (nitrofural, stavudine, quinine and quinidine) are non-antibiotics showing promising predicted antitubercular activity. Most of these molecules have the similar privileged antimycobacterial drugs scaffold. Further drug likeness properties were calculated to get deeper insights to M.tb lead molecules. Interestingly, it was also observed that the drugs identified from the study are under different stages of drug discovery (i.e., in vitro, clinical trials) for the effective treatment of various diseases including cancer, degenerative diseases, dengue virus infection, tuberculosis, etc. Krasavin et al., 2017 synthesized nitrofuran analogues with appreciable MICs (22–23 µM) against M.tb H37Rv. These experiments further add to the credibility of the drugs identified in this study (TB). Graphic Abstract: [Figure not available: see fulltext.].
KW - Drug repositioning
KW - M.tb targets
KW - PASS
KW - Polypharmacology
KW - Virtual screening
UR - http://www.scopus.com/inward/record.url?scp=85114038308&partnerID=8YFLogxK
U2 - 10.1007/s11030-021-10296-2
DO - 10.1007/s11030-021-10296-2
M3 - Article
C2 - 34468898
AN - SCOPUS:85114038308
SN - 1381-1991
VL - 26
SP - 1675
EP - 1695
JO - Molecular Diversity
JF - Molecular Diversity
IS - 3
ER -