title: Discovery of newMycobacterium tuberculosisproteasome inhibitors using a knowledge-based computational screening approach.
abstract: Mycobacterium tuberculosis bacteria cause deadly infections in patients [Corrected]. The rise of multidrug resistance associated with tuberculosis further makes the situation worse in treating the disease. M. tuberculosis proteasome is necessary for the pathogenesis of the bacterium validated as an anti-tubercular target, thus making it an attractive enzyme for designing Mtb inhibitors. In this study, a computational screening approach was applied to identify new proteasome inhibitor candidates from a library of 50,000 compounds. This chemical library was procured from the ChemBridge (20,000 compounds) and the ChemDiv (30,000 compounds) databases. After a detailed analysis of the computational screening results, 50 in silico hits were retrieved and tested in vitro finding 15 compounds with IC₅₀ values ranging from 35.32 to 64.15 μM on lysate. A structural analysis of these hits revealed that 14 of these compounds probably have non-covalent mode of binding to the target and have not reported for anti-tubercular or anti-proteasome activity. The binding interactions of all the 14 protein-inhibitor complexes were analyzed using molecular docking studies. Further, molecular dynamics simulations of the protein in complex with the two most promising hits were carried out so as to identify the key interactions and validate the structural stability.
authors.affiliation: Discovery Informatics Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Rukmankesh
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Clinical Microbiology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Reena
authors.initials: R
authors.lastname: Chib
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Gurunadham
authors.initials: G
authors.lastname: Munagala
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Kushalava Reddy
authors.initials: KR
authors.lastname: Yempalla
authors.affiliation: Clinical Microbiology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Inshad Ali
authors.initials: IA
authors.lastname: Khan
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Parvinder Pal
authors.initials: PP
authors.lastname: Singh
authors.affiliation: Clinical Microbiology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India. fairygk@rediffmail.com.
authors.forename: Farrah Gul
authors.initials: FG
authors.lastname: Khan
authors.affiliation: Discovery Informatics Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India. amitnargotra@yahoo.com.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India. amitnargotra@yahoo.com.
authors.forename: Amit
authors.initials: A
authors.lastname: Nargotra
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D061988:Proteasome Inhibitors; D054852:Small Molecule Libraries
keywords: In silico screening; Mycobacterium tuberculosis inhibitors; Pharmacophore modeling; Proteasome inhibitors; QSAR; Similarity search