Structure based drug design and molecular modeling

Introduction

1. Pharmaceutical research topics

• new products with enhanced activity
• new products with diminished side effects
• need of new products by increasing resistance

but on the other side:

• high development costs
• unfavourable ratio between synthesized compounds and products on the market

 

A 10.000 Candidates B 100 PreClinical C 5 Clinical   1 New Drug

=> takes 7-10 years to come to market with a new drug and costs ~ $ 150-800 million !
 

Hope:

new computational techniques will improve the drug pipeline weed out candidates early in the process discover bad candidates as soon as possible in order to safe costs



• extremely expensive test procedures required (preclinical and clinical tests)

 

clinical tests
phase I	tests on healthy males (pharmacokinetics, pharmacodynamics, toxicity)
phase II	tests on a limited number of persons with specific disease (efficacy)
phase III	global tests on broad clinical basis (definite safety, optimal dosage)
phase IV	registration, market support

2. Structure-Based Drug Design

Drug design and drug discovery are of critical importance in human health care. Their success depends on insights and advances from the combined use of chemical and biological research. Computational approaches have become a major part of rational drug design and are generally combined with structural information derived from macromolecular crystallography and nuclear magnetic resonance investigations. More recently, new methods of synthesizing very large libraries of potentially bioactive small molecules through combinatorial methods have possess screening strategies into increasingly important roles in drug discovery. To test these large arrays of molecules complementary biological innovations have been required. Because of the enormously data explosion of genomic information new fields have arisen in the drug design process, such as pharmacogenetics and pharmacogenomics.

In applying a rational approach to a drug design project, scientists perform experiments to gain greater understanding of drug-receptor interactions in order to delineate the different molecular forces involved in binding interactions and the molecular recognition process. This is particularly important in addressing species specificity for a particular biological system.

Rational Drug Design = a strategy-based approach

understanding the pathological and biochemical aspects of the disease

identifying the target enzyme or receptor, and the mechanism of action

determine or predict the structure of the target enzyme or receptor

design and/or identify the lead compound

optimization of the biological activity by using the structure of the target enzyme or receptor

1. direct methods => direct docking of potential ligands into a 3D model of a receptor
2. indirect methods => extract 3D information from the structures that assay as active/inactive
3. combinatorial methods => use of high throughput screening with combinatorial design and synthesis of compound libraries to rapidly detect and refine drug leads

Discovery of drugs

• from natural products (digitaline, taxol, etc. ...)
• by discovery (chlordiazepoxide, aspartame, etc. ...)
• by chance (viagra etc. ...)
• by structure-activity relationships (most)
• by rational design (since the 80‘s)
• by systematic screening (since the 90‘s)

Additional information

More information about Molecular Modelling and Drug Design you will find under the following links:

• Biocomputing and Drug Design (by W. Altenhofen)
• Ruben Abagyan Research Group (The Scripps Research Institute (TSRI), La Jolla)

Home	My Drug Design Website