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

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.