Molecular dynamics simulations for the structure-based drug design: targeting small-GTPases proteins.
Expert Opin Drug Discov
; 19(10): 1259-1279, 2024 Oct.
Article
in En
| MEDLINE
| ID: mdl-39105536
ABSTRACT
INTRODUCTION:
Molecular Dynamics (MD) simulations can support mechanism-based drug design. Indeed, MD simulations by capturing biomolecule motions at finite temperatures can reveal hidden binding sites, accurately predict drug-binding poses, and estimate the thermodynamics and kinetics, crucial information for drug discovery campaigns. Small-Guanosine Triphosphate Phosphohydrolases (GTPases) regulate a cascade of signaling events, that affect most cellular processes. Their deregulation is linked to several diseases, making them appealing drug targets. The broad roles of small-GTPases in cellular processes and the recent approval of a covalent KRas inhibitor as an anticancer agent renewed the interest in targeting small-GTPase with small molecules. AREA COVERED This review emphasizes the role of MD simulations in elucidating small-GTPase mechanisms, assessing the impact of cancer-related variants, and discovering novel inhibitors. EXPERT OPINION The application of MD simulations to small-GTPases exemplifies the role of MD simulations in the structure-based drug design process for challenging biomolecular targets. Furthermore, AI and machine learning-enhanced MD simulations, coupled with the upcoming power of quantum computing, are promising instruments to target elusive small-GTPases mutations and splice variants. This powerful synergy will aid in developing innovative therapeutic strategies associated to small-GTPases deregulation, which could potentially be used for personalized therapies and in a tissue-agnostic manner to treat tumors with mutations in small-GTPases.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Design
/
Molecular Dynamics Simulation
/
Neoplasms
/
Antineoplastic Agents
Limits:
Humans
Language:
En
Journal:
Expert Opin Drug Discov
Year:
2024
Document type:
Article
Affiliation country:
Italia
Country of publication:
Reino Unido