Recent advances in multitarget-directed ligands via in silico drug discovery

• Published in: Drug discovery today 2024-03, Vol.29 (3), p.103904-103904, Article 103904
• Main Authors: Maddeboina, Krishnaiah, Yada, Bharath, Kumari, Shikha, McHale, Cody, Pal, Dhananjaya, Durden, Donald L.
• Format: Article
• Language: English
• Subjects: Drug Design; Drug Discovery; in silico drug discovery; kinase inhibitors; Ligands; multitarget drugs; Pharmaceutical Preparations; Polypharmacology; small molecules; Structure-Activity Relationship; synthetic lethality
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2024.103904

•Strategies to develop multitarget-directed ligands via in silico drug discovery.•The effects of multidirectional drugs are more favorable than those of single-target or combination treatments on drug resistance, pharmacokinetics, pharmacodynamics, safety, and cost effectiveness.•The use of multitarget drugs can increase therapeutic efficacy by targeting multiple signaling pathways and addressing complex diseases with multiple underlying causes and dominant resistance mechanisms.•The drugs can be designed to avoid off-target effects, which can lead to reduced side effects and enhanced efficacy compared to single target agents. To combat multifactorial refractory diseases, such as cancer, cardiovascular, and neurodegenerative diseases, multitarget drugs have become an emerging area of research aimed at ‘synthetic lethality’ (SL) relationships associated with drug-resistance mechanisms. In this review, we discuss the in silico design of dual and triple-targeted ligands, strategies by which specific ‘warhead’ groups are incorporated into a parent compound or scaffold with primary inhibitory activity against one target to develop one small molecule that inhibits two or three molecular targets in an effort to increase potency against multifactorial diseases. We also discuss the analytical exploration of structure–activity relationships (SARs), physicochemical properties, polypharmacology, scaffold feature extraction of US Food and Drug Administration (FDA)-approved multikinase inhibitors (MKIs), and updates regarding the clinical status of dual-targeted chemotypes.