Recent trends in search for novel pharmaceutical agents have focused on the preparation of small molecule libraries as potential sources of new lead compounds for drug discovery. Several powerful chemical and biological techniques have been developed for this purpose. This thesis presents an advanced method of constructing combinatorial library, which was demonstrated by generating twenty-five compounds through reductive amination with a set of five aldehyde derivatives and a set of five secondary amine derivatives. It was presented as three sets of sublibraries in which each of the reagent cumulatively reacted with the corresponding substrates as normal-diagonal, reversed-diagonal and crossed-diagonal methods in order to deduced the most active compound exactly and efficiently. This diagonal library could provide intrinsic effectiveness that had never been favored in the orthogonal or indexed library known. The diagonal library was designed to have four approaching directions within the matrix, while conventional techniques had only two approaching directions. Thereby, we could improve the possibility of finding true active compound discovery because they had intrinsically acquired additional checking means. As a result, we could reduce the inexactness that associated with surveying true lead compound from libraries.
The binding mode of ligand to GPCR was studied by searching the relationship between spacial homology of guanine protein coupled receptors(GPCR) and affinity values of potent ligands. Until now, binding mode studies have just focused on pharmacopores of various ligands for the fixed binding site. However, while matching the parameters analyzed statistically from spacial homology comparison and the corresponding parameter obtained from real experimental binding data, we became to propose a new idea that the active site might significantly reorganize according to ligand structures. We had an assumption that such a reorganization would be associated with minimum change of orientation of seven transmembrane helices. Afterward, we compared selected potent compounds for adrenergic receptor subtypes; alpha- la/ lb/ lc, and then for dopamine/ serotonine receptors. We have found several different binding mode of different types of ligands for the same GPCR. We could deduce the virtual pockets through simple statistical comparison technique.
본 논문은 대각선형 조합화학을 이용하여 새로운 선도 물질을 얻고자 하는데 목적이 있었다. 종래의 rationale synthesis는 신물질을 얻는데 오랜 시간과 많은 비용의 측면에서 비효율성이 있었다. 따라서 본 논문은 신물질 합성에 있어 종래의 방법을 보완하면서 신속하고 효율적으로 선도물질을 합성하는 방법을 제시하였고 실제로 Dopamine antagonist를 모델 합성하여 이의 유효성을 증명하고자 하였다.
이를 위해서 조합화학이라는 새로운 분야에서 접근을 시도하였다. 조합화학은 여러 종류의 단위체로 부터 수많은 종류의 화합물을 합성하고 적합한 검색 수단을 사용하여 최적의 활성 화합물을 발견하는 방법이다. 그리하여 본 논문에서는 GPCR(guanine protein coupled receptor)중에서 biogenic amines을 리간드로 하는 5-Hydroxytryptamine receptor, Adrenergic receptor 들의 알려진 antagonist를 disconnection하여 이들을 기본 골격으로 5 가지의 아릴 알데히드와 5 가지의 아릴 아민으로 나누어 모델 합성의 단위체로 사용하였다.
단위체간의 커플링 반응에서는 Sodium triacetoxyborohydride를 사용하여 좋은 수율과 상온에서 25 종의 화합물을 얻을 수 있었다. 특히 검색의 효율성과 정확도를 높이기 위하여 대각선형 방향에서 누적합성을 하였으며 이렇게 함으로써 활성 검색시 파생되는 몇가지 오류들을 극복할 수 있었고 신물질 보다 효율적으로 합성하는 기반을 제시해 주었다
