Current Progress in Structure-Based Rational Drug Design Marks a New Mindset in Drug Discovery

Abstract

The past decade has witnessed a paradigm shift in preclinical drug discovery with structure-based drug design (SBDD) making a comeback while high-throughput screening (HTS) methods have continued to generate disappointing results. There is a deficit of information between identified hits and the many criteria that must be fulfilled in parallel to convert them into preclinical candidates that have a real chance to become a drug. This gap can be bridged by investigating the interactions between the ligands and their receptors. Accurate calculations of the free energy of binding are still elusive; however progresses were made with respect to how one may deal with the versatile role of water. A corpus of knowledge combining X-ray structures, bioinformatics and molecular modeling techniques now allows drug designers to routinely produce receptor homology models of increasing quality. These models serve as a basis to establish and validate efficient rationales used to tailor and/or screen virtual libraries with enhanced chances of obtaining hits. Many case reports of successful SBDD show how synergy can be gained from the combined use of several techniques. The role of SBDD with respect to two different classes of widely investigated pharmaceutical targets: (a) protein kinases (PK) and (b) G-protein coupled receptors (GPCR) is discussed. Throughout these examples prototypical situations covering the current possibilities and limitations of SBDD are presented.

Pyrazolyl-Tetrazoles and Imidazolyl-Pyrazoles as Potential Anticoagulants and their Integrated Multiplex Analysis Virtual Screening

“…46 Particularly, global electrostatics and ionized microspecies of potential ligands should be considered prior to any structural evaluation, while taking into account the specific pH in which the target enzyme is mostly found. 47 By enriching our molecular library with ligand-based filters such as water availability, complementary electrostatics to the target enzyme and proper biodistribution, it is expected for the 5a-g series to display a predictive anticoagulant activity, as generally observed for several other ligands with respect to their target.…”

Rapid Screening by Cell-Based Fusion Assay for Identifying Novel Antivirals of Glycoprotein B-Mediated Herpes Simplex Virus Type 1 Infection

“…Identification of novel antiviral compounds should be dependent on an in vitro primary assay for high-throughput screening (HTS) of the compound libraries. 30) In addition, structure-based drug design (SBDD) could be a powerful tool, 31) especially for identifying novel inhibitors of viruses. 32) We are currently performing this cell-based fusion assay for the screening of small chemical compounds from the library against HSV-1 infection, in combination with SBDD.…”

Structure-based drug design approach to target toll-like receptor signaling pathways for disease treatment

“…The genes for these targets can then be cloned, and protein products can be synthesized and purified for use. The three-dimensional structures of proteins used to determine potential drug targets are derived through a number of techniques, and the efficiency of these techniques has improved in recent years [1]. Below, the principles behind choosing drug targets and determining the threedimensional structures of those targets will be reviewed.…”