SPECIFICITY IN STRUCTURE-BASED DRUG DESIGN - IDENTIFICATION OF A NOVEL, SELECTIVE INHIBITOR OF PNEUMOCYSTIS-CARINII DIHYDROFOLATE-REDUCTASE

Specificity is an important aspect of structure-based drug design, Dis tinguishing between related targets in different organisms is often th e key to therapeutic success, Pneumocystis carinii is a fungal opportu nist which causes a crippling pneumonia in immunocompromised individua ls, We report the identification of novel inhibitors of P. carinii dih ydrofolate reductase (DHFR) that are selective versus inhibition of hu man DHFR using computational molecular docking techniques, The Fine Ch emicals Directory, a database of commercially available compounds, was screened with the DOCK program suite to produce a list of potential I ! carinii DHFR inhibitors, We then used a postdocking refinement direc ted at discerning subtle structural and chemical features that might r eflect 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 mu M in an enzyme assay, These inhib itors were further assayed against human DHFR: 10 of the 13 (77%) bind preferentially to the fungal enzyme, The most potent compound identif ied is a 7 mu M inhibitor of P, carinii DHFR with 25-fold selectivity, The ability of molecular docking methods to locate selective inhibito rs reinforces our view of structure-based drug discovery as a valuable strategy, not only for identifying lead compounds, but also for addre ssing receptor specificity. (C) 1997 Wiley-Liss, Inc.