title: Structure-based virtual screening as a tool for the identification of novel inhibitors against Mycobacterium tuberculosis 3-dehydroquinate dehydratase.
abstract: 3-Dehydroquinate dehydratase (DHQase), the third enzyme of the shikimate pathway, catalyzes the reversible reaction of 3-dehydroquinate into 3-dehydroshikimate. The aim of the present study was to identify new drug-like molecules as inhibitors for Mycobacterium tuberculosis DHQase employing structure-based pharmacophore modeling technique using an in house database consisting of about 2500 small molecules. Further the pharmacophore models were validated using enrichment calculations, and finally three models were employed for high-throughput virtual screening and docking to identify novel small molecules as DHQase inhibitors. Five compounds were identified, out of which, one molecule (Lead 1) showed 58% inhibition at 50μ M concentration in the Mtb DHQase assay. Chemical derivatives of the Lead 1 when tested evolved top two hits with IC50s of 17.1 and 31.5 μM as well as MIC values of 25 and 6.25 μg/mL respectively and no cytotoxicity up to 100 μM concentration.
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF), Instituto Nacional de Ciência e Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681, 90619-900 Porto Alegre, Brazil; Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Porto Alegre 90619-900, Brazil; Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors.forename: Guilherme O
authors.initials: GO
authors.lastname: Petersen
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Saxena
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors.forename: Janupally
authors.initials: J
authors.lastname: Renuka
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Soni
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF), Instituto Nacional de Ciência e Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681, 90619-900 Porto Alegre, Brazil; Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Porto Alegre 90619-900, Brazil.
authors.forename: Diogenes S
authors.initials: DS
authors.lastname: Santos
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF), Instituto Nacional de Ciência e Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681, 90619-900 Porto Alegre, Brazil; Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Porto Alegre 90619-900, Brazil. Electronic address: cristiano.bizarro@pucrs.br.
authors.forename: Cristiano V
authors.initials: CV
authors.lastname: Bizarro
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D066264:Datasets as Topic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D008024:Ligands; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase
keywords: DHQase; Drug discovery; Shikimate pathway; Tuberculosis; Virtual screening