Atsushi Kasuya

Interaction between peroxisome proliferator-activated receptor γ and its agonists: docking study of oximes having 5-benzyl-2,4-thiazolidinedione

The molecular modelling of oximes having 5-benzyl-2,4-thiazolidinedione moieties, agonists of the peroxisome proliferator-activated receptor gamma (PPAR gamma), was performed with respect to their structures complexed with the ligand binding domain of PPAR gamma. For each ligand molecule, the 5-benzyl-2,4-thiazolidinedione head group was used as an anchor and the conformation of the rest of the molecule was searched for the most energetically favorable interaction with the receptor by systematic conformation search and manual modelling. Although both tail-up and tail-down configurations, which have been observed in the crystal structure of eicosapentaenoic acid when complexed with PPAR delta, appeared among the lowest energy structures for most of the compounds, potent agonists were found to adopt a configuration similar to that of rosiglitazone when bound to PPAR gamma, according to the crystal structure. The structure-activity relationships were analyzed based on the receptor-ligand interaction. The alkyl group and the aromatic ring of the tail group of the ligands had hydrophobic interactions with the receptor, and these interactions were found to be essential for the strong activity.

Structure–activity relationship of HIV-1 protease inhibitors containing α-hydroxy-β-amino acids. Detailed study of P1 site

Abstract The structure–activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing α-hydroxy-β-amino acids is discussed. We demonstrated that substituent groups on the P 1 aromatic rings of the inhibitors exert significant influence on their biological activity. Inhibitors bearing an alkyl or a fluorine atom at the meta and para position on their P 1 benzene ring were found to be good inhibitors. We also discovered that the substitution positions of the P 2 benzamides were crucial for good antiviral potency. In this study, inhibitor 48 was the most potent {IC 90 (CEM/HIV-1 IIIB) 27 nM} and showed good pharmacokinetics in rats.

Structure–activity relationship of HIV-1 protease inhibitors containing AHPBA. Part III: modification of P2 site

The structure-activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing AHPBA (3-amino-2-hydroxy-4-phenylbutanoic acid) is discussed. In order to solve the problem of poor oral bioavailability, small-sized dipeptide HIV-1 protease inhibitors containing cyclic urethanes or benzamides at the P2 site were designed and prepared. The substitution patterns of the benzamides contributed significantly to their HIV-1 PR inhibitory activities, and it was shown that the choice of P2-residues was very important. Highly potent inhibitors possessing subnanomolar IC50 values and exhibiting good antiviral potency have been identified. In this class, inhibitor 18 was the most potent (IC90 (CEM/HIV-1 IIIB) 0.11 microM) and showed good oral bioavailability in dogs.

An Efficient Method for Reconstructing Protein Backbones from Alpha-Carbon Coordinates

We present an approach for building protein backbones from alpha-carbon (Calpha) coordinates. The approach is analytical and based on the information of favored regions in the Ramachandran map. The backbone construction consists of three parts: prediction of (phi, psi) angle pairs from the Calpha trace, generation of atomic coordinates with these (phi, psi) angles, and refinement by subsequent energy minimization. Tests on several known protein structures show that the root mean square deviations in reconstructed backbones are 0.25-0.48 A for coordinates and 14-34 degrees for phi and psi angles. The results indicate that our method is one of the best methods proposed in terms of accuracy. It has also been revealed that the approach is not only robust against errors in Calpha coordinates but is also capable of providing equivalent or more reasonable models compared to other known methods. Furthermore, backbone structures were found to be built accurately by using the (phi, psi) angles from a different structure of the same protein. This suggests that the approach could be effective and useful in homology modeling studies.