【摘要】：新藥創(chuàng)制是復(fù)雜的智力活動,涉及科學(xué)研究、技術(shù)創(chuàng)造、產(chǎn)品開發(fā)和醫(yī)療效果等多維科技活動。每個藥物都有自身的研發(fā)軌跡,而構(gòu)建化學(xué)結(jié)構(gòu)是最重要的環(huán)節(jié),因?yàn)樗w了藥效、藥代、安全性和生物藥劑學(xué)等性質(zhì)。本欄目以藥物化學(xué)視角,對有代表性的藥物的成功構(gòu)建,加以剖析和解讀。20世紀(jì)90年代在基于靶標(biāo)結(jié)構(gòu)設(shè)計(jì)藥物(SBDD)的研究中,沙奎那韋是為數(shù)不多成功的一個。由于解析了HIV蛋白酶的作用機(jī)制和酶的三維結(jié)構(gòu),研究者得以從最簡單的基本單元入手,在成藥性理念的指導(dǎo)下,"生長"成與活性中心的形狀、尺寸和電性呈互補(bǔ)結(jié)合的擬肽鏈,同時"注入"過渡態(tài)的類似結(jié)構(gòu),完成了首創(chuàng)的高活性的口服抗艾滋病藥物沙奎那韋。進(jìn)而研發(fā)者針對該首創(chuàng)藥物的不足,繼續(xù)在結(jié)構(gòu)生物學(xué)的指引下,研制成活性更強(qiáng)、藥代完善和克服耐藥的兩個更新產(chǎn)品。安普那韋和地瑞那韋在同一理念下研制成功,但無論在宏觀生物學(xué)和化學(xué)性質(zhì)上,還是微觀的結(jié)合特征和熱力學(xué)的焓-熵轉(zhuǎn)化方面,都更勝一籌。
[Abstract]:New drug creation is a complex intellectual activity involving multi-dimensional scientific and technological activities such as scientific research, technological creation, product development and medical effects. Each drug has its own R & D track, and the construction of chemical structures is the most important step because it covers pharmacodynamics, pharmacology, safety and biopharmaceutical properties. This column analyzes and interprets the successful construction of representative drugs from the perspective of pharmacochemistry. In the 1990s, in the research of drug design based on target structure, Zaquinavir is one of the few successful drugs. By analyzing the mechanism of HIV protease and the three-dimensional structure of the enzyme, the researchers were able to start with the simplest basic unit and, guided by the idea of drug formation, "grow" and shape the active center. Size and electrical properties of the complementary binding peptide chain, at the same time "injection" of the transition state of similar structures, completed the first highly active oral anti-AIDS drug Zaquinavir. In order to overcome the shortage of the original drug, the researchers continue to develop two new products with stronger activity, better pharmacokinetics and better drug resistance under the guidance of structural biology. Amponavir and denavir have been successfully developed under the same concept, but they are superior in macroscopic biological and chemical properties, microcosmic combination characteristics and enthalpy entropy transformation of thermodynamics.
【作者單位】： 中國醫(yī)學(xué)科學(xué)院、北京協(xié)和醫(yī)學(xué)院藥物研究所;
【分類號】：R91

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