Sm. Wang et al., DISCOVERY OF NOVEL, NONPEPTIDE HIV-1 PROTEASE INHIBITORS BY PHARMACOPHORE SEARCHING, Journal of medicinal chemistry, 39(10), 1996, pp. 2047-2054
Fifteen novel non-peptide HIV-1 protease inhibitors were identified by
flexible 3D database pharmacophore searching of the NCI DIS 3D databa
se. The pharmacophore query used in the search was derived directly fr
om the X-ray determined structures of protease/inhibitor complexes. Th
ese 15 inhibitors, belonging to nine different chemical classes, are p
romising leads for further development. The two best inhibitors found,
NSC 32180, a ''dimer'' of 4-hydroxycoumarin, and NSC 117027, a ''tetr
amer'' of 2-hydroxy quinone, had ID50 values of 0.32 and 0.75 mu M for
HIV-1 protease inhibition, respectively, and two other inhibitors had
ID50 values close to 1 mu M. Among the potent inhibitors, NSC 158393
not only demonstrated activity against HIV-1 protease (ID50 1.7 mu M)
but also exhibited promising antiviral activity in HIV-1-infected CEM-
SS cells (EC(50) = 11.5 mu M). Validation of the pharmacophore used in
the search was accomplished by conformational analysis. The binding m
odes of the most potent inhibitor found in our studies, NSC 32180, wer
e predicted employing docking and molecular dynamics techniques.