Drug-likeness analysis of traditional Chinese medicines: 2. Characterization of scaffold architectures for drug-like compounds, non-drug-like compounds, and natural compounds from traditional Chinese medicines

Sheng Tian 1 Youyong Li 1 Junmei Wang 2 Xiaojie Xu 3 Lei Xu 1 Xiaohong Wang 1 Lei Chen 1 Tingjun Hou 0 1 0 College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China 1 Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University , Suzhou, Jiangsu 215123, China 2 Department of Biochemistry, The University of Texas Southwestern Medical Center , 5323 Harry Hines Blvd., Dallas, TX 75390, USA 3 College of Chemistry and Molecular Engineering, Peking University , Beijing 100871, China Background: In order to better understand the structural features of natural compounds from traditional Chinese medicines, the scaffold architectures of drug-like compounds in MACCS-II Drug Data Report (MDDR), non-drug-like compounds in Available Chemical Directory (ACD), and natural compounds in Traditional Chinese Medicine Compound Database (TCMCD) were explored and compared. Results: First, the different scaffolds were extracted from ACD, MDDR and TCMCD by using three scaffold representations, including Murcko frameworks, Scaffold Tree, and ring systems with different complexity and side chains. Then, by examining the accumulative frequency of the scaffolds in each dataset, we observed that the Level 1 scaffolds of the Scaffold Tree offer advantages over the other scaffold architectures to represent the scaffold diversity of the compound libraries. By comparing the similarity of the scaffold architectures presented in MDDR, ACD and TCMCD, structural overlaps were observed not only between MDDR and TCMCD but also between MDDR and ACD. Finally, Tree Maps were used to cluster the Level 1 scaffolds of the Scaffold Tree and visualize the scaffold space of the three datasets. Conclusion: The analysis of the scaffold architectures of MDDR, ACD and TCMCD shows that, on average, drug-like molecules in MDDR have the highest diversity while natural compounds in TCMCD have the highest complexity. According to the Tree Maps, it can be observed that the Level 1 scaffolds present in MDDR have higher diversity than those presented in TCMCD and ACD. However, some representative scaffolds in MDDR with high frequency show structural similarities to those in TCMCD and ACD, suggesting that some scaffolds in TCMCD and ACD may be potentially drug-like fragments for fragment-based and de novo drug design. - Introduction Natural products are generally considered as a rich source of biologically active substances [1]. Many drugs approved by the Food and Drug Administration (FDA) directly come from natural products. In the period of 19812002, 5% of the 1031 new chemical entities (NCE) approved as drugs by the FDA are natural products, and other 23% are natural-product-derived molecules [2]. Historically, 60% of cancer drugs and 75% of infectious disease drugs are derived from natural products [2]. Because natural products have been selected during evolution to bind to various proteins during their life-cycle, they are good starting points for drug discovery [3,4]. Traditional Chinese medicines (TCMs) are primarily based on a large number of herbal formulations that are used for the treatment of a wide variety of diseases. The discovery of hits or leads from natural compounds in TCMs has become a feasible and popular strategy in modern drug discovery pipelines [2]. With the rapid development of high-throughput screening (HTS) and combinatorial synthesis, it becomes possible to generate and evaluate tens of thousands of compounds in a very short period of time with relatively low cost. Unfortunately, the new drugs approved by the FDA did not soar in recent years and even declined slightly, and even only one de novo combinatorial compound was approved in the last 25 years before 2007 [5]. This low success rate may be partly caused by low chemotype, limited scaffold diversity and lack of biological relevant scaffolds of combinatorial compounds [6]. Therefore, searching and designing molecule collections with novel scaffolds and high structural diversity will offer more opportunities for molecules to become leads, and ultimately to become new drugs. It is believed that natural compounds are a good source of novel molecular scaffolds [2,5,7-9] and the scaffolds derived from natural compounds have preferable or privileged scaffold architectures [10]. Since the scaffolds of natural compounds are potentially valuable, how to characterize and define the scaffolds that are meaningful for drug design/discovery is the center question we are facing now. It is well known that ring systems form the cornerstone of molecules, and they determine the basic shapes and flexibilities of molecules [11]. In drug design process, ring systems are usually used as the core or central scaffolds to build virtual libraries, and the ring systems in known active compounds can usually be replaced or modified to find new active candidates by using the scaffold hopping (...truncated)