Prodrug Design vs. Drug Design
Rafik Karaman · Drug Designing Open Access · 2013
Drug discovery is a lengthy interdisciplinary endeavor. It is a consecutive process that commences with target and lead discovery, followed by lead optimization and pre-clinical in vitro and in vivo studies to evaluate if a compound satisfies a number of pre-set criteria to start clinical development [7-8]. The number of years it takes to introduce a drug to the pharmaceutical market is about 10 years with a cost of up to $1 billion dollars. Traditionally, drugs were discovered by a time-consuming multi-step synthetic process which was followed by in vivo biological screening and further investigation for the promising compounds in terms of their Absorption, Distribution, Metabolism, Excretion (ADME) properties, and potential toxicity. Such drug development processes have resulted in high attrition rates with failures attributed to poor pharmacokinetic properties, lack of efficacy, toxicity, side effects in humans, and various commercial factors [7-8]. Nowadays, the process of drug discovery has been revolutionized with the advent of genomics, proteomics, bioinformatics, and efficient technologies including combinatorial chemistry, High Throughput Screening (HTS), virtual screening, de novo design, in vitro, in silico ADME screening, and structure-based drug design [9-11]. Structurebased drug design is widely considered one of the most innovative and powerful approaches in drug design. It is an approach that requires a 3D structure of the target protein with or without a hosted ligand, where binding mode, affinity, and confirmation of ligand binding can be discerned. Various computational methods are used to design a high-affinity inhibitor either via virtual computer screening of large compound libraries or through design and synthesis of novel ligands. These methods can also be utilized to analyze the target structures for possible binding/active sites, generate candidate structures, check for their drug-likeness, dock structures with the target, rank according to their binding affinities, and optimize the molecules to improve binding properties.