The identification of novel Mycobacterium tuberculosis DHFR inhibitors and the investigation of their binding preferences by using molecular modelling

• DOI: 10.1038/srep15328
• Publication Date: 2015-10-16T08:59:02Z
• Authors: Wei Hong; Yu Wang; Zhe Chang; Yanhui Yang; Jing Pu; Tao Sun; Sargit Kaur; James C. Sacchettini; Hunmin Jung; Wee Lin Wong; Lee Fah Yap; Yun Fong Ngeow; Ian C. Paterson; Hao Wang
• Keywords: Glycerol; 0301 basic medicine; Molecular Conformation; Dihydrofolate reductase; Microbial Sensitivity Tests; FOS: Health sciences; DNA Topoisomerases: Structure, Function, and Inhibition; Biochemistry; Gene; Article; Molecular model; Binding site; Computational biology; Structure-Activity Relationship; 03 medical and health sciences; FOS: Chemical sciences; Stereochemistry; Biochemistry, Genetics and Molecular Biology; Health Sciences; Chemistry and Pharmacology of Quinazoline Compounds; Pathology; Humans; Tuberculosis; Molecular Biology; Biology; Binding Sites; Active site; Organic Chemistry; In silico; Life Sciences; Hydrogen Bonding; Mycobacterium tuberculosis; Recombinant Proteins; Anti-Bacterial Agents; Protein Structure, Tertiary; 3. Good health; Molecular Docking Simulation; Tetrahydrofolate Dehydrogenase; Chemistry; Infectious Diseases; Enzyme; Drug Design; Physical Sciences; Folic Acid Antagonists; Thermodynamics; Medicine

AbstractIt 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.