ABSTRACT
An approach to drug design and lead generation is presented which attempts to retain the qualities of traditional drug design and leave control with the bench scientist, whilst harnessing the power of computers to handle the combinatorial explosion of ideas. A computer language, ALEMBIC, is used to collate the ideas of the scientists. The resulting list of potential molecules is then parameterised using whole molecule descriptors. Based on these descriptors, appropriate statistical techniques are used to generate sets of molecules retaining the maximum amount of the information inherent in all possible combinations of the scientists ideas.
Subject(s)
Drug Design , Models, Chemical , Models, Molecular , AnimalsABSTRACT
X-ray crystallography studies of racemic 5-[7-[4-(4,5-dihydro-4-methyl-2-oxazolyl)phenoxy]heptyl]- 3-methylisoxazole bound to human rhinovirus-14 (HRV-14) indicate selective binding of the S isomer. This result correlates well with the 10-fold greater activity of the S isomer as compared to the R isomer. The enantiomeric effect on activity is explained by a hydrophobic interaction of the methyl group in the case of 2a, with a pocket formed by Leu106 and Ser107. The 4-ethyl, 4-propyl, and 4-butyloxazolinyl homologues were prepared and tested against HRV-14. All of these compounds exhibited a comparable stereochemical effect. In each case, the S isomer displayed greater levels of activity than the R. The results of energetic considerations of the oxazoline ring in an 8-A pocket bound to the HRV-14 binding site suggest that the twist angle between the oxazoline and phenyl rings resulting from hydrophobic interactions of the alkyl substituents could be one of the determining factors for biological activity.
Subject(s)
Antiviral Agents/pharmacology , Isoxazoles/pharmacology , Oxazoles/pharmacology , Rhinovirus/drug effects , Computer Simulation , Humans , Models, Molecular , Stereoisomerism , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
A series of substituted phenyl analogues of 5-[[4-(4,5-dihydro-2-oxazolyl) phenoxy]alkyl]-3-methylisoxazoles has been synthesized and evaluated in vitro against several human rhinovirus (HRV) serotypes. Substituents in the 2-position greatly enhanced activity when compared to the unsubstituted compound. Many of these compounds exhibited mean MICs (MIC) against five serotypes as low as 0.40 microM. The mean MIC correlated well (r = 0.83) with the MIC80 (the concentration that inhibited 80% of the serotypes tested). A quantitative structure-activity relationship study indicated a strong dependency of MIC on lipophilicity (log P) in combination with inductive effects (sigma m) and bulk factors (MW).
