In the era of post-genomics, computer is a powerful tool of aiding drug design and exploring useful information in databases. Due to the high cost of developing new drugs, computer aided drug design have been widely used in drug discovery and lead compound optimization. In this thesis we try to deduce some guidelines of drug design and drug target discovery for zinc-containing proteins and ADP-ribosyltransferases, as these enzymes are important drug targets for various diseases such as cancer, bacteria infections, bacterial resistance to antibiotics, rheumatoid arthritis, diabetes, and endotoxic shock.
Chapter 2. We reveal the physical basis for the observed differences between structural and catalytic Zn□sites: In most catalytic sites, water is found bound to Zn2+ as it transfers the least charge to Zn2+ and is less bulky compared to the protein ligands, enabling Zn2+ to serve as a Lewis acid in catalysis. In most structural sites, however, ≥2 Cys□□□ are found bound to Zn2+, as Cys□□ transfers the most charge to Zn2+ and reduces the Zn charge to such an extent that Zn2+ can no longer act as a Lewis acid; furthermore, steric repulsion among the bulky Cys(S□□) prevents Zn2+ from accommodating another ligand.
Chapter 3. We discuss the differential effects of commonly observed Zn-His-Bkb vs. Zn-His-[Asp/Glu] triad on Zn-core stability and reactivity. We also reveal the advantage of a second-shell Asp/Glu carboxylate in catalytic Zn-cores: relative to a Bkb carbonyl group, it increases (i) the HOMO energy of the cationic/neutral zinc core, (ii) the reactivity of the attacking Zn-bound OH□, (iii) electron transfer to the substrate, and (iv) the stability of the metal complex upon electron transfer.
Chapter 4. We discover a conserved structural motif for recognizing nicotinamide adenine dinucleotide in poly(ADP-ribose) polymerases and ADP-ribosylating toxins and discuss the implications for structure□based drug design. This locally conserved structure binds the nicotinamide mononucleotide moiety in a structurally conserved ring□like conformation. The biological implications/applications of locally conserved structures for toxins/PARPs and the nicotinamide mononucleotide are discussed.

在後基因時代，電腦是幫助我們搜尋資料庫以及輔助藥物設計的強大的工具。它可以降低藥物開發的高成本，並且替我們從大量資料庫中篩選出可能的藥物結構或者藥物標靶。因此，我們在本論文針對兩種重要蛋白質，並利用量子化學理論計算以及分子模擬揭櫫了電腦輔助藥物設計的原理原則。在本論文中我們探討兩大類重要的蛋白質。第一種是含鋅蛋白質，此類蛋白質已經被廣泛利用來治療癌症，細菌抗藥性，類風濕性關節炎以及糖尿病等疾病。第二種是二磷酸腺苷核糖轉移酶，這個酵素是近幾年來被廣為研究而且被視為可以治療難治癌症的藥物標靶，有許多家知名藥廠已經針對這個酵素推出許多抑制劑，目前已經有一些抑制劑已通過第二期的臨床試驗。
在第二章我們揭櫫了二價的鋅離子在結構功能與催化功能結合位置中有不同的物理化學性質。由於鋅離子主要扮演路易士酸的角色，Cys在與鋅離子結合時相對於其他常見的胺基酸，會傳送最多的電荷給金屬，導致鋅離子成為微弱路易士酸，使得鋅結合位置成為結構功能的角色。相反的，催化功能的鋅結合位置不常與Cys鍵結，使得此結合位置的鋅離子適合扮演催化的角色。
在第三章我們討論了在催化功能的鋅結合位置Zn-His-Bkb與 Zn-His-[Asp/Glu] 三聚體。後者常見於催化角色而前者卻較少發現，我們利用理論計算探討了其中的原因。
在第四章我們在二磷酸腺苷核糖轉移酶的催化中心歸納出共同的構形，此構形外觀貌似一隻蠍子，故命名為蠍子構形。在本章我們分析了二磷酸腺苷核糖轉移酶主要運用蠍子構形來辨識她的受體，並且在蠍子構形頭與尾部提供了較強的的凡得瓦作用力跟NAD+結合。此外我們也發現NAD+與二磷酸腺苷核糖轉移酶結合的時候會形成一個特殊的構形，此構形可以幫助吾人設計更有抑制力的藥物。最後我們利用蠍子構形彼此在三度空間相似的特點，發展了一個將藥物結構或NAD+放入二磷酸腺苷核糖轉移酶結合位置的準確並簡單的方法。此方法可以幫物吾人在電腦輔助藥物設計上對能量與結合常數有更正確的估計，以期設計更有抑制力的藥物。

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