title: Identification of chebulinic acid as potent natural inhibitor of M. tuberculosis DNA gyrase and molecular insights into its binding mode of action.
abstract: Drug resistant tuberculosis has threatened all the advances that have been made in TB control at the global stage in the last few decades. DNA gyrase enzymes are an excellent target for antibacterial drug discovery as they are involved in essential functions like DNA replication. Here we report, a successful application of high throughput virtual screening (HTVS) to identify an inhibitor of Mycobacterium DNA gyrase targeting the wild type and the most prevalent three double mutants of quinolone resistant DNA gyrase namely A90V+D94G, A74S+D94G and A90V+S91P. HTVS of 179.299 compounds gave five compounds with significant binding affinity. Extra presicion (XP) docking and MD simulations gave a clear view of their interaction pattern. Among them, chebulinic acid (CA), a phytocompound obtained from Terminalia chebula was the most potent inhibitor with significantly high XP docking score, -14.63, -16.46, -15.94 and -15.11 against wild type and three variants respectively. Simulation studies for a period of 16 ns indicated stable DNA gyrA-CA complex formation. This stable binding would result in inhibition of the enzyme by two mechanisms. Firstly, binding of CA causes displacement of catalytic Tyr129 away from its target DNA-phosphate molecule from 1.6 Å to 3.8-7.3 Å and secondly, by causing steric hindrance to the binding of DNA strand at DNA binding site of enzyme. The combined effect would result in loss of cleavage and religation activity of enzyme leading to bactericidal effect on tuberculosis. This phytocompound displays desirable quality for carrying forward as a lead compound for anti-tuberculosis drug development. The results presented here are solely based on computations and need to be validated experimentally in order to assert the proposed mechanism of action.
authors.affiliation: Department of Biotechnology, Delhi Technological University, Delhi 110042, India.
authors.forename: Kunal
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan 304022, India.
authors.forename: Chetna
authors.initials: C
authors.lastname: Tyagi
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan 304022, India.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Goyal
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan 304022, India.
authors.forename: Salma
authors.initials: S
authors.lastname: Jamal
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Divya
authors.initials: D
authors.lastname: Wahi
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Ritu
authors.initials: R
authors.lastname: Jain
authors.affiliation: Department of Biotechnology, Delhi Technological University, Delhi 110042, India.
authors.forename: Navneeta
authors.initials: N
authors.lastname: Bharadvaja
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. Electronic address: abhinavgr@gmail.com.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D027081:DNA Gyrase / Q000378:metabolism*; D004269:DNA, Bacterial / Q000378:metabolism; D057166:High-Throughput Screening Assays; D047348:Hydrolyzable Tannins / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D047348:Hydrolyzable Tannins; C103481:chebulinic acid; D027081:DNA Gyrase
keywords: Chebulinic acid; DNA gyrase; Molecular dynamics simulations; Multiple drug resistance; Tuberculosis; Virtual screening