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Mechanism of activation and the rewired network: New drug design concepts
Author(s) -
Nussinov Ruth,
Zhang Mingzhen,
Maloney Ryan,
Tsai ChungJung,
Yavuz Bengi Ruken,
Tuncbag Nurcan,
Jang Hyunbum
Publication year - 2022
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.21863
Subject(s) - mechanism (biology) , drug , computational biology , mechanism of action , drug discovery , identification (biology) , biology , genetics , bioinformatics , pharmacology , philosophy , botany , epistemology , in vitro
Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology . Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same‐allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure‐based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor‐specific network, ushering innovative considerations in precision medicine.