Specificity in structure‐based drug design: Identification of a novel, selective inhibitor of Pneumocystis carinii dihydrofolate reductase

Abstract

Specificity is an important aspect of structure-based drug design. Distinguishing between related targets in different organisms is often the key to therapeutic success. Pneumocystis carinii is a fungal opportunist which causes a crippling pneumonia in immunocompromised individuals. We report the identification of novel inhibitors of P. carinii dihydrofolate reductase (DHFR) that are selective versus inhibition of human DHFR using computational molecular docking techniques. The Fine Chemicals Directory, a database of commercially available compounds, was screened with the DOCK program suite to produce a list of potential P. carinii DHFR inhibitors. We then used a postdocking refinement directed at discerning subtle structural and chemical features that might reflect species specificity. Of 40 compounds predicted to exhibit anti-Pneumocystis DHFR activity, each of novel chemical framework, 13 (33%) show IC50 values better than 150 microM in an enzyme assay. These inhibitors were further assayed against human DHFR: 10 of the 13 (77%) bind preferentially to the fungal enzyme. The most potent compound identified is a 7 microM inhibitor of P. carinii DHFR with 25-fold selectivity. The ability of molecular docking methods to locate selective inhibitors reinforces our view of structure-based drug discovery as a valuable strategy, not only for identifying lead compounds, but also for addressing receptor specificity.

Inhibitors of Kinesin Activity from Structure-Based Computer Screening

“…The inhibitors presented in our study are similar to selective anthraquinone-, phenolphthalein-, and fluoresceinbased inhibitors presented in other structure-based computer screening studies of other enzyme systems (15,45,46). The inhibitors in Table 1 contain common cores of various known enzyme inhibitors and drugs.…”

Structure-Based Identification of Small Molecule Antiviral Compounds Targeted to the gp41 Core Structure of the Human Immunodeficiency Virus Type 1

“…Therefore, close visual inspection with stereoglasses of the top-scoring molecules individually for appropriate interactions is necessary. 29,49 Sixteen of the 200 best-scoring compounds were tested by ELISA for inhibitory activity on the formation of the N-36/C-34 complex using mAb NC-1 and on HIV-1 infection, including HIV-1-mediated cell fusion and CPE, and for in vitro cytotoxicity ( Table 1) To find out the energetic feasibility of the CONCORD program-generated conformations used for the dock runs, conformational analysis of both ADS-J1 and ADS-J2 was performed by a systematic conformational search in the Sybyl program. The best 1000 conformers for each compound were selected for docking runs.…”

HIV Entry Inhibitors Targeting gp41: From Polypeptides to Small-Molecule Compounds

“…We used the force field scoring method, rather than a shape based scoring method, to rank the best possible compounds for docking into the pocket. About 200 compounds with top scores were selected for indepth inspection of the interactions at the hydrophobic pocket and neighboring regions by molecular visualization techniques [69,70]. We then selected 16 best scoring compounds for testing their inhibitory activity on the 6-HB formation between N36 and C34 by the sandwich ELISA using the mAb NC-1 [25,26] and on HIV-1 infection, including HIV-1-mediated cell-cell fusion and HIV-1 replication as previously described [13,71].…”