Pharmacokinetic Study of a Novel Antihyperlipidemic Agent LM-13765- A Prodrug

A sensitive and specific high performance thin layer chromatographic method has been developed for estimation of a novel antihyperlipidemic agent LM 13765 in rabbit plasma and its use for pharmacokinetic study has been evaluated. The proposed method was employed to study pharmacokinetics of LM 13765 in rabbits. It was observed that LM 13765 metabolized immediately after oral administration. The metabolite of LM 13765 was identified and characterized as LM 13765-C. A sensitive and specific HPTLC method was developed for estimation of LM 13765-C in plasma after oral administration of LM 13765 and pharmacokinetic parameters were determined. Biological screening of LM 13765-C on hyperlipidemic rats indicated that it is less potent than the parent compound which is indicative of biotransformation of LM 13765 to active form LM 13765-C

Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines

We present comprehensive testing of solvent representation in quantum mechanics (QM)-based scoring of protein-ligand affinities. To this aim, we prepared 21 new inhibitors of cyclin-dependent kinase 2 (CDK2) with the pyrazolo[1,5-a]pyrimidine core, whose activities spanned three orders of magnitude. The crystal structure of a potent inhibitor bound to the active CDK2/cyclin A complex revealed that the biphenyl substituent at position 5 of the pyrazolo[1,5-a]pyrimidine scaffold was located in a previously unexplored pocket and that six water molecules resided in the active site. Using molecular dynamics, protein-ligand interactions and active-site water H-bond networks as well as thermodynamics were probed. Thereafter, all the inhibitors were scored by the QM approach utilizing the COSMO implicit solvent model. Such a standard treatment failed to produce a correlation with the experiment (R(2) = 0.49). However, the addition of the active-site waters resulted in significant improvement (R(2) = 0.68). The activities of the compounds could thus be interpreted by taking into account their specific noncovalent interactions with CDK2 and the active-site waters. In summary, using a combination of several experimental and theoretical approaches we demonstrate that the inclusion of explicit solvent effects enhance QM/COSMO scoring to produce a reliable structure-activity relationship with physical insights. More generally, this approach is envisioned to contribute to increased accuracy of the computational design of novel inhibitors