Ball MD, Meshnick SR, Bartlett MS, Shaw M, Nasr M, Smith JW; American Society for Microbiology. General Meeting.
Abstr Gen Meet Am Soc Microbiol. 1999 May 30-Jun 3; 99: 320 (abstract no. F-124).
Rose-Hulman Institute of Technology, Terre Haute, IN.
For 21 monomeric naphthoquinone derivatives, molecular modeling was used to define the relationship between chemical structure and in vitro activity against Pneumocystis carinii. With various substituents at position 3, there were sixteen 2-hydroxy derivatives, one 2-hydroxy- 7-methoxy, one 2-methyl, four 2-chloro, and one 2-amino. All compounds were compared to the active derivative atovaquone (ATQ) in the lowest-energy conformation (strain energy=4.93 kcal/mol) found by the SYBYL force field. In this conformation, the naphthoquinonyl and phenyl rings are coplanar, with each being perpendicular to and equatorial on the cyclohexyl ring. Comparison of accessible conformations for all 21 compounds revealed a structure-activity pattern wherein antipneumocystis activity parallels the ability of a molecule to conformationally fit its 3-substituent to the van der Waals space occupied by the 3-substituent of ATQ. Without invoking the other substituents at positions 2 and 7, this hypothesis posits three simultaneous structural conditions for activity. First, the molecule must superimpose at least three of its atoms on three atoms in ATQ's cyclohexyl ring, or it must otherwise occupy space inside that ring. Second, the molecule must extend volume into the planar space occupied by ATQ's phenyl ring; this is unnecessary, however, if the molecule has a cyclohexyl ring directly superimposable on that of ATQ. Third, the molecule must not project steric bulk equatorially from the space corresponding to ATQ's cyclohexyl ring or perpendicularly from the phenyl ring. This hypothesis may prove useful in the rational design of anti-Pneumocystis agents with lower IC50 values.
Publication Types:
Keywords:
- Atovaquone
- Computer Simulation
- In Vitro
- Models, Molecular
- Molecular Conformation
- Motor Activity
- Naphthoquinones
- Pneumocystis
- Pneumonia, Pneumocystis
Other ID:
UI: 102195717
From Meeting Abstracts