| Institution: | 1. Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA;2. Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA;3. Department of Chemistry, Stanford University, Stanford, CA 94305, USA;4. Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA;5. Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA;1. RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan;2. RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan;3. RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan;4. RIKEN Program for Drug Discovery and Medical Technology Platforms, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan;5. School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan;1. Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China;2. Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;3. Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China;1. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea;2. Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea;3. Division of Applied RI, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea |
| Abstract: | Currently available volumes of compounds and biological activity data enable large-scale analyses of compound promiscuity (multi-target activity). To aid in the exploration of structure-promiscuity relationships, promiscuity cliffs (PCs) were introduced previously. In analogy to activity cliffs, PCs were defined as pairs of structurally analogous compounds with large differences in the number of targets they are active against. Hence, PCs reveal small chemical modifications that are implicated in promiscuity. As introduced originally, PCs were identified by applying the matched molecular pair formalism and were thus confined to changes at a single substitution site. Herein, PCs with multiple substitution sites are introduced and a pilot study on a large collection of protein kinase inhibitors is reported, which provide excellent test cases for promiscuity analysis. For dual-site PCs (dsPCs), which dominated the distribution of multi-site PCs, an extended data structure was generated comprising a dsPC and two single-site analogs accounting for individual substitutions. Using a canonical representation, extended dsPCs are intuitive and easy to interpret from a chemical perspective. The analog quartet representing an extended dsPC is rich in structure-promiscuity relationship information and makes it possible to evaluate the potential interplay of chemical modifications implicated in promiscuity. Furthermore, extended dsPCs provide insights into possible experimental causes of apparent differences in analog promiscuity such as varying test frequencies. Hence, the newly introduced PC format should be of interest for exploring origins of compound promiscuity in medicinal chemistry and for formulating experimentally testable target hypotheses for analogs. |
