Most of the current approved drugs block receptors/enzymes by competing with agonists/substrates for binding to the same pocket. While this type of drugs revolutionized health care since the advent of the modern pharmaceutical industry, the accumulating research in complex diseases such as cancer highlighted the limitations of such drugs in certain environmental context.

Novel strategies have been employed to circumvent those limitations and offer a superior pharmacological profile. In this PhD thesis, we employed computer-assisted drug discovery tools to help guiding and designing three binders that do not follow the traditional drug profile: a PROTAC to target HIF2α in the context of renal cell carcinoma, a covalent drug to offer an alternative to anti-TNFα biologics and a negative allosteric modulator to tune A2AR activation by adenosine and improve the immune system efficacy in the tumor micro-environment.