Structure-Based Drug Design in Drug Discovery
Common drug targets
The majority of available drugs have protein molecules as their targets. Although nucleic acids may also be considered, their use as drug targets in drug discovery and structure based drug design has been limited due to various effects like toxicity, difficulty in achieving high specificity, etc. In a survey of currently available marketed drugs, it was shown that out of the 21 000 registered in the USA drugs, only 1357 were unique. Of these 1204 were small-molecule drugs, while 166 were biological agents. The total number of protein drug targets, which included both human proteins and proteins from pathogenic organisms, was found to be 324. Of these 207 were human protein drug targets (Overington, Al-Lazikani & Hopkins, 2006). Around 70% of the targets belonged to 10 protein families, while almost 50% of the drugs were shown to exert their activity via 4 families: G-protein coupled receptors, nuclear receptors, ligand-gated and voltage-gated ion channels. Looking at the structural side, the authors used the CATH and SCOP databases, which contain classification of protein domains, and identified 130 “druggable” domains. This a nice example of how structural bioinformatics resources are used in drug discovery and structure-based drug design.
SARomics Biostructures provides a full-range contract drug discovery and drug design service, including protein crystallization in complex with ligands provided by the client, gene-to-structure services, etc., please contact us at SARomics Biostructures to discuss your project. The KINOMED Partnership, also provides specific services related to kinase drug discovery as well as of-the-shelf kinase structures.
Starting a structure-based drug discovery project
Most modern drug discovery projects start with protein target identification and verification to obtain a “verified drug target”. For structure-based drug design the three-dimensional structure of the protein in question needs to be determined by one of the available high resolution experimental methods: Protein crystallography or NMR. In addition to general questions on protein structure and function, in a drug discovery project one needs answer more specific questions like:
Does the target protein belong to a biochemical pathway, which can be bypassed by the cell, if inhibited?
If the protein target belongs to a pathogen, are there any related proteins in the human host, which may be affected by the drug?
Does the drug target has a small-molecule binding site, and if it does, are there any compounds available, which have been demonstrated to bind to that site?
Is there any X-ray or NMR three-dimensional structure available of the protein target in question? If not, is there any structure available of a homologous protein, which can be used for homology modeling?
If it is an antibiotic or anti-fungal agent being designed, one could also ask: Taking into account the nature of the target, how broad specificity across species the new inhibitor compound can be expected to have?
Most of these and other questions related to drug discovery and structure based drug design may be answered using the tools of bioinformatics in general, and structural bioinformatics in particular. For example, a simple database search in combination with sequence alignment will answer the second question. The same applies to most other questions. In the following page we will discuss in more details the questions related to finding a useful compound (lead generation) and the use of structural information in compound structure optimization.
Most modern drug discovery projects start with protein target identification and verification to obtain a “verified drug target”. For structure-based drug design the three-dimensional structure of the protein in question needs to be determined by one of the available high resolution experimental methods: Protein crystallography or NMR. In addition to general questions on protein structure and function, in a drug discovery project one needs answer more specific questions like:
Does the target protein belong to a biochemical pathway, which can be bypassed by the cell, if inhibited?
If the protein target belongs to a pathogen, are there any related proteins in the human host, which may be affected by the drug?
Does the drug target has a small-molecule binding site, and if it does, are there any compounds available, which have been demonstrated to bind to that site?
Is there any X-ray or NMR three-dimensional structure available of the protein target in question? If not, is there any structure available of a homologous protein, which can be used for homology modeling?
If it is an antibiotic or anti-fungal agent being designed, one could also ask: Taking into account the nature of the target, how broad specificity across species the new inhibitor compound can be expected to have?
Most of these and other questions related to drug discovery and structure based drug design may be answered using the tools of bioinformatics in general, and structural bioinformatics in particular. For example, a simple database search in combination with sequence alignment will answer the second question. The same applies to most other questions. In the following page we will discuss in more details the questions related to finding a useful compound (lead generation) and the use of structural information in compound structure optimization.
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Based on competence and long-standing experience, Red Glead Discovery offers first-rate research services for drug discovery. In-house laboratory capabilities comprise medicinal chemistry, biology, analytical chemistry and ADME. An expert area is generation of chemical starting points for drug targets and to develop them into patentable lead compounds with drug-like properties and low risk profile. Our project management skills and cross-disciplinary capabilities make us a preferred partner for clients that want to develop compounds with high potential to become successful drugs. |