Eiichi Akaho

A comparative study of AutoDock and PMF scoring performances, and SAR of 2-substituted pyrazolotriazolopyrimidines and 4-substituted pyrazolopyrimidines as potent xanthine oxidase inhibitors

Abstract4-Alkylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, 4-arylmethylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, and 2-substituted 7H-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidines as potential xanthine oxidase inhibitors were docked into the active site of the bovine milk xanthine dehydrogenase using two scoring functions involved in AutoDock 3.05 and the CAChe 6.1.10. The correlation coefficiency obtained between the AutoDock binding energy and IC50 of the inhibitors was better than that obtained by the CAChe-PMF docking score. Many ligands exhibited one to four hydrogen bonds within the active site, where the detected hydrogen bonds by CAChe was identified quantitatively in the docked conformation by using MOPAC 2002. These ligands were docked into a long, narrow channel of the enzyme leading to the molybdopterin active moiety, with hydrogen bonding and electrostatic interaction between the planar aromatic moiety of the ligand and the enzyme. Furthermore, SAR among inhibitors was investigated, which revealed that the oxo group of pyrazolopyrimidine analogs is essential for its activity and the tricyclic derivatives are shown to be more potent than bicyclic ones. The mode of interaction of the docked inhibitors was described in details.

Synthesis and receptor docking studies of N-substituted indole-2-carboxylic acid esters as a search for COX-2 selective enzyme inhibitors

A series of N-substituted indole-2-carboxylic acid esters have been prepared by replacing the benzoyl group of indomethacin with a benzyl and a phenyl group. The carbocyclic acid side chain was extended via creating an ester structure by using several dialkylaminoalkyl groups. The receptor docking studies were performed to investigate the docking mode of each compound by using DOCK 4.0. All the compounds were shown to be docked at the site where intact flurbiprofen was embedded for COX-1 and s-58 (1-phenylsulphonamide-3-trifluoromethyl-5-para-bromophenylpyrazole) for COX-2. It was predicted that N-phenyl-indole-2-carboxylic acid piperazine ester 22 can be a fairly strong COX-2 selective compound which was compared to the others. Other predicted COX-2 selective compounds included are N--H indole-2-carboxylic acid diethyl 30 and piperazine 34 esters. In view of these findings, compounds 22, 30 and 34 were chosen for the in vitro biological assays.

Evaluation of Indole Esters As Inhibitors of p60c-Src Receptor Tyrosine Kinase and Investigation of the Inhibition Using Receptor Docking Studies

Several indole esters were tested as inhibitors of tyrosine kinase p60c-Src. Compound (4) was found fairly active against the enzyme with IC50=1.34 μM. DOCK methodology was used to asses our inhibitors for their inhibitory potency against tyrosine kinase. The docking results showed that compounds (4), (25) and (26) were bound to the active site of the enzyme Lys 295 of p60c-Src tyrosine kinase. Both activity and docking studies showed a parallel result, with compound (4) having a better interaction with the enzyme active site and also greater activity than the other compounds, indicating a potential role as new lead inhibitor.

Structure-based drug design and AutoDock study of potential protein tyrosine kinase inhibitors.

Different classes of compounds were investigated for their binding affinities into different protein tyrosine kinases (PTKs) employing a novel flexible ligand docking approach by using AutoDock 3.05 and 4. These compounds include many flavin analogs, which were developed in our group with varying degrees of cytotoxic activity (comparable or moderately superior to cisplatin and ara-c), and database selected analogs. They were docked onto twelve different families of PTKs retrieved from the Protein Data Bank. These proteins are representatives of plausible models of interactions with chemotherapeutic agents. A comparative study of the intact co-crystallized ligands of various types of PTKs was carried out. Results revealed that the new class of 5-deazapteridine and steroid hybrid compounds VIa,b, and d, and the vertical-type bispyridodipyrimidine with n-hexyl chain junction between its N-10 and N-10 atoms Xa, exhibited non-selective PTK binding capacities, with the lowest (Gb). On the other hand, 2-amino benzoic acid analog IIa, phenoxypyrido [3, 4-d]pyrimidine derivative IVc, tyrosine containing tripeptide Vd, and the one from Sumisho data base 831 are proposed to have selective PTK binding affinities to certain classes of tyrosine kinases, namely, HGFR (c-met), ZAP-70, insulin receptor kinase, EGFR, respectively. All These compounds of highest affinities were docked within the binding sites of PTKs with reasonable RMSD and 1-5 hydrogen bonds.

Japanese Pharmacy: Innovation Mixed with Tradition

Objective: To report the current status of pharmacy practice in Japan. Data Sources: Published conference reports, journal articles, human resource consultation with medical and pharmacy practitioners, and site visitation by the authors. Data Extraction And Synthesis: Data on areas related to Japanese history, practice of pharmacy, and professional innovations were obtained through interviews and the literature. Information is provided to give an appreciation of current pharmacy practice in Japan. Conclusions: Japanese pharmacy practice is a strong combination of tradition and professional innovation. The potential for professional growth is immense; Japanese pharmacy has successfully established payment for nondistributive pharmacy services. Payment for cognitive services creates many positive incentives for the future practice of pharmacy in Japan.

Studies on 16α-Hydroxylation of Steroid Molecules and Regioselective Binding Mode in Homology-Modeled Cytochrome P450-2C11

We investigated the 16α-hydroxylation of steroid molecules and regioselective binding mode in homology-modeled cytochrome P450-2C11 to correlate the biological study with the computational molecular modeling. It revealed that there was a positive relationship between the observed inhibitory potencies and the binding free energies. Docking of steroid molecules into this homology-modeled CYP2C11 indicated that 16α-hydroxylation is favored with steroidal molecules possessing the following components, (1) a bent A-B ring configuration (5β-reduced), (2) C-3 α-hydroxyl group, (3) C-17β-acetyl group, and (4) methyl group at both the C-18 and C-19. These respective steroid components requirements were defined as the inhibitory contribution factor. Overall studies of the male rat CYP2C11 metabolism revealed that the above-mentioned steroid components requirements were essential to induce an effective inhibition of [3H]progesterone 16α-hydroxylation. As far as docking of homology-modeled CYP2C11 against investigated steroids is concerned, they are docked at the active site superimposed with flurbiprofen. It was also found that the distance between heme iron and C16α-H was between 4 to 6 Å and that the related angle was in the range of 180 ± 45°.

American and Japanese Drug Distribution and Information Systems in 1994 and a Proposed System for Improved Pharmaceutical Care

Drug distribution environments were reported in the United States and Japan. It was observed that both countries are readily adjusting to rapidly changing drug distribution environments. In the United States direct marketing and purchasing practices have been growing while in Japan very few of these practices are seen. Mandated cost containment by health care companies has influenced pharmacy operation patterns in the United States such as mail order pharmacies and managed-care-controlled pharmacies, while in Japan pharmacy operations are likely to be overwhelmed by the long-standing physician dispensing practices. Patients hope that competition created from a variety of practices results in improved pharmaceutical care for them. Neither system of drug distribution practices is superior to the other. Both Japanese and American pharmacy practices must continually evolve to meet their own social, economic, and professional needs and standards of practice.

Computer experiences and attitudes of Japanese pharmacy students

The purpose of this study was to evaluate the computer experiences and attitudes of first- and fourth-year Japanese pharmacy students. An existing questionnaire that asked questions about computer hardware and software owned, reported level of expertise with software applications, attitudes and concerns about computers, and demographic information was translated into Japanese. After ensuring the accuracy of the translation, first- and fourth-year pharmacy students completed the survey. This study found that most of these Japanese pharmacy students did not frequently use computers. About one-quarter of the students owned a home computer. Slightly more than 10% of the students reported that they could use word processing programs. Their attitudes about computers were positive. Most stated that they should possess basic computer skills when graduating from pharmacy school. The students also indicated that they would rather learn from computers than attend lectures or read texts or journals. However, 63 first-year (32%) and 45 fourth-year (43.7%) students said that microcomputers were too complicated for them to use

An International Comparison of Teratogen Consultation Systems (Motherisk and Toranomon) and a Proposed Optimal System with an Innovative Risk Calculation Formula

The Canadian Motherisk Program is so well-organized that it can be regarded as a representative teratogen consultation system outside of Japan. The Toranomon Hospitals system is a similar system within Japan. By studying various characteristics of the two systems an optimal system was proposed with an innovative risk calculation formula. In the proposed optimal system, one should consider such factors as system follow-up, versatile computer back-up, global coverage of people, easy access to the system, well-controlled documentation, sufficient and up-to-date information collection, financial support by health insurance, manpower back-up in different specialties, and security protection. An innovative risk calculation formula is a product of risk points of the drug itself and administration-time risk points of the particular drug in question.

A comparative study of free information retrievals and a suggested sensible approach to the Internet by adopting a specific search topic apoptosis

A comparative study of information retrieval from the Internet was pursued by adopting a specific search topic “apoptosis.” The search engines and databases used were those without a service charge. The search process was examined from a sensible perspective. One hundred and forty-five records were retrieved from Lycos and 490 from Open Text. Those two were fairly comprehensive search tools. EINet and Galaxy provided six and 14 records and were not as comprehensive tools as Lycos and Open Text. As far as scientific articles were concerned, UnCover was superior to the others. Yahoo provided no record. It served as a guide, however, to other relevant sources. The Internet provides access to a vast collection of mixed information and data. One gets lost quite easily and it is necessary to “surf” skillfully and smoothly in order to reach the target of ones own search. A sensible perspective was used for the introductory search of the Internet. This sensible approach was represented in the form of a flow chart; by following the chart one can “surf” safely and effectively so as to reach the destination of the search with an optimum result.