Discovery of Mycobacterium tuberculosis α-1,4-glucan branching enzyme (GlgB) inhibitors by structure- and ligand-based virtual screening.
GlgB (α-1,4-glucan branching enzyme) is the key enzyme involved in the biosynthesis of α-glucan, which plays a significant role in the virulence and pathogenesis of Mycobacterium tuberculosis. Because α-glucans are implicated in the survival of both replicating and non-replicating bacteria, there exists an exigent need for the identification and development of novel inhibitors for targeting enzymes, such as GlgB, involved in this pathway. We have used the existing structural information of M. tuberculosis GlgB for high throughput virtual screening and molecular docking. A diverse database of 330,000 molecules was used for identifying novel and efficacious therapeutic agents for targeting GlgB. We also used three-dimensional shape as well as two-dimensional similarity matrix methods to identify diverse molecular scaffolds that inhibit M. tuberculosis GlgB activity. Virtual hits were generated after structure and ligand-based screening followed by filters based on interaction with human GlgB and in silico pharmacokinetic parameters. These hits were experimentally evaluated and resulted in the discovery of a number of structurally diverse chemical scaffolds that target M. tuberculosis GlgB. Although a number of inhibitors demonstrated in vitro enzyme inhibition, two compounds in particular showed excellent inhibition of in vivo M. tuberculosis survival and its ability to get phagocytosed. This work shows that in silico docking and three-dimensional chemical similarity could be an important therapeutic approach for developing inhibitors to specifically target the M. tuberculosis GlgB enzyme.
From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India and.
Hedwin Kitdorlang
HK
Dkhar
the Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
Anupriya
A
Gopalsamy
From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India and.
Saurabh
S
Loharch
From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India and.
Amandeep
A
Kaur
From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India and.
Isha
I
Bhutani
the Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
Kanmani
K
Saminathan
From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India and.
Ella
E
Bhagyaraj
From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India and.
Vemika
V
Chandra
the Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
Kunchithapadam
K
Swaminathan
From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India and.
Pushpa
P
Agrawal
From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India and rparkesh@imtech.res.in.
Raman
R
Parkesh
From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India and pawan@imtech.res.in.
Pawan
P
Gupta
D015061:1,4-alpha-Glucan Branching Enzyme / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D062313:Databases, Pharmaceutical; D030562:Databases, Protein; D055808:Drug Discovery; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005936:Glucans / Q000737:chemistry / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D010587:Phagocytosis / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D005936:Glucans; D008024:Ligands; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; C040088:1,4-glucan; D015061:1,4-alpha-Glucan Branching Enzyme
Docking; Molecular Docking; Mycobacterium tuberculosis; Pathogenesis; Small Molecule