Introduction: A major challenge for drug design is the alarming increase in drug resistance, mutations and toxicity. In recent years, covalent drugs have become a promising option to address these problems, due to their significant advantages. These advantages include their ability to target rare, non-conserved residues, shallow binding sites of target proteins and their ability to retain their binding with a receptor for a very long time.
Areas covered: This review shows the increasing progress in rational design and virtual screening of covalent drugs and the promising future of accurately predicting effective covalent drugs through in silico screening.
Expert opinion: All the current clinically approved covalent drugs were discovered by chance instead of systematic design. There is a promising and commendable effort towards high-throughput screening and the accurate discovery of new covalent inhibitors, which may address the problems of drug resistance and mutation. However, despite the current progression, there is still a need for more rational attention to improve the covalent warhead for improved receptor interaction and selectivity.
Keywords: covalent warheads; docking; high-throughput; rational design; selectivity.