Identification Of And System Profile Analysis On The Therapeutic Targets In The Human Kinome

Intensive efforts in exploring novel targets from the genome of human or pathogen have discovered hundreds of established, hundreds of clinical trial, and thousands of research drug targets. Over the past two decades, the kinases have become one of the most productive protein classes of therapeutic targets, but only a small portion of the human kinome has been established to yield approved drugs. Due to the emerging necessities for treating complex diseases by the means of network pharmacology, it is of great interests to identify novel efficacious target from the human kinome. Moreover, the majority of FDA approved drugs against kinase was developed only for cancer treatment. Further efforts were therefore spent for releasing its therapeutic potential by discovering new therapeutic area or identifying novel kinase targets. In this study, comprehensive collection of target data was conducted, and key features distinguishing single target drugs from the multiple target ones, FDA approved drugs from the clinical trial ones were identified. Detailed steps followed by this study were listed as below.Firstly, this study updated the Therapeutic Targets Database(TTD). In this work, TTD's coverage has been significantly expanded to 723 clinical trial targets and 9 528 drugs in clinical trial, which makes TTD the most comprehensive and accurate database in providing the information of clinical trial drugs and targets. Meanwhile, this work enhanced TTD's applicability by adding 2 071 approved, 17 803 experimental drugs linked to their corresponding 397 successful, 2 589 research targets. Moreover, this version of TTD provided the comprehensive cross-links among 1 433 targets,19 671 drugs and 2 096 signaling pathways, which provided reliable data for researchers in the field of network pharmacology.Secondly, key features distinguishing the multi-target drugs from the combination ones targeting the human kinome were compared. The drug-target interaction networks were drawn and analyzed. VEGFR2 and c-Kit, EGFR and human DNA were identified as the most popular therapeutic targets of approved multi-target drugs and combination products, respectively. A comparative analysis of the phylogenetic tree of target pairs aimed by the multi-target drugs and the combination products revealed that the approved multi-target drugs inhibited target pairs in the human kinome, while the combination products tended to target much more diverse sets of target pairs. Diseases treated by both multi-target drugs and combination products were identified to generate sub-network of drug-target interactions. Popular efficacious targets of the same disease were explored.Lastly, key features distinguishing the system profiles of the established kinase targets from that of clinical trial ones were identified. As discovered, the successful kinase targets tend to be similar to fewer human proteins outside of their target family, associate with fewer human pathways, express in fewer human tissues. To guarantee the efficacy and safety of developed drugs, the systems profiles of the majority of clinical trial kinases were identified to be similar to those of established ones. Furthermore, the structural and physicochemical properties of FDA approved and clinical trial small molecular kinase inhibitors were assessed, which showed that their molecular weight were in the range of 350-600 and their total ring count were between 3 and 5.