title: The identification of novel Mycobacterium tuberculosis DHFR inhibitors and the investigation of their binding preferences by using molecular modelling.
abstract: It is an urgent need to develop new drugs for Mycobacterium tuberculosis (Mtb), and the enzyme, dihydrofolate reductase (DHFR) is a recognised drug target. The crystal structures of methotrexate binding to mt- and h-DHFR separately indicate that the glycerol (GOL) binding site is likely to be critical for the function of mt-DHFR selective inhibitors. We have used in silico methods to screen NCI small molecule database and a group of related compounds were obtained that inhibit mt-DHFR activity and showed bactericidal effects against a test Mtb strain. The binding poses were then analysed and the influence of GOL binding site was studied by using molecular modelling. By comparing the chemical structures, 4 compounds that might be able to occupy the GOL binding site were identified. However, these compounds contain large hydrophobic side chains. As the GOL binding site is more hydrophilic, molecular modelling indicated that these compounds were failed to occupy the GOL site. The most potent inhibitor (compound 6) demonstrated limited selectivity for mt-DHFR, but did contain a novel central core (7H-pyrrolo[3,2-f]quinazoline-1,3-diamine), which may significantly expand the chemical space of novel mt-DHFR inhibitors. Collectively, these observations will inform future medicinal chemistry efforts to improve the selectivity of compounds against mt-DHFR.
authors.affiliation: School of Chemistry and Chemical Engineering, Beifang University of Nationalities, Yinchuan, 750021, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hong
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, P. R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, P. R. China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chang
authors.affiliation: School of Basic Medicine, Ningxia Medical University, Yinchuan, 750004, P. R. China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Pu
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, P. R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Pre-Clinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Bandar Sungei Long, 43000, Malaysia.
authors.forename: Sargit
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Department of Biochemistry and Biophysics, Texas A &M University, College Station, TX 77843, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.affiliation: Department of Biochemistry and Biophysics, Texas A &M University, College Station, TX 77843, USA.
authors.forename: Hunmin
authors.initials: H
authors.lastname: Jung
authors.affiliation: Department of Oral Biology and Biomedical Sciences and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, 50603, Malaysia.
authors.forename: Wee
authors.initials: W
authors.lastname: Lin Wong
authors.affiliation: Department of Oral Biology and Biomedical Sciences and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, 50603, Malaysia.
authors.forename: Lee
authors.initials: L
authors.lastname: Fah Yap
authors.affiliation: Department of Pre-Clinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Bandar Sungei Long, 43000, Malaysia.
authors.forename: Yun
authors.initials: Y
authors.lastname: Fong Ngeow
authors.affiliation: Department of Oral Biology and Biomedical Sciences and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, 50603, Malaysia.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Paterson
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, P. R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D005990:Glycerol / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D011994:Recombinant Proteins; D013762:Tetrahydrofolate Dehydrogenase; D005990:Glycerol