Identifying new chemical structures against protein targets of interest represents one of the major challenges in drug discovery. As the major experimental method, high throughput screenings are performed with existing chemical libraries, thus restricting its capability to explore high molecular diversity. Herein, we report the use of high throughput array synthesis technology, in combination with growth algorithm, to discover binders for proinflammatory cytokine TNF-α. After 6 iterations of Library design – Array synthesis – Screening (i-LAS), one identified compound T17 has shown a kd value of 14.8 μM, and can rescue L929 cells from TNF-α mediated cytotoxicity. Further engineering T17 in various forms of oligomers have led to low nM binders. More interestingly, through tuning the multi-valent interaction with TNF-α, the high affinity oligomers can be switched from inhibitors to activators, leading to the hypothesis of an oligomerization-induced receptor activation mechanism. The i-LAS technology has allowed us to discover new binder structures, which can be further engineered into molecules with novel properties.