Bioinformatics Ayesha M. Khan Spring 2013

Phylogenetic software PHYLIP l 2

In silico drug design  Help in identifying and analyzing drug targets via bioinformatics tools. Computer aided drug design (CADD)  Specialized discipline that uses computational methods to simulate drug interactions  Dependent on bioinformatics tools, applications and databases. 3

Structural Bioinformatics Bioinformatics offers a means to obtain a structure through sequence while structure aided drug design offers a means to get a drug through structure. In particular bioinformatics and structure based drug design are providing important information about the structure, function and pharmaceutical potential of many earlier unknown or uncharacterized proteins and ligands. “Structural bioinformatics” (SBI) ◦ A subset of bioinformatics concerned with the use of biological structures-proteins, DNA, RNA, ligands, etc., and complexes thereof to strengthen our understanding of biological systems. 4

SBI in Drug Design and Discovery SBI can be used to examine:  drug targets (usually proteins)  binding of ligands ↓ “rational” drug design (benefits = saved time and $$$) 5

Traditional Methods of Drug Discovery natural (plant-derived) treatment for illness/ailments ↓ isolation of active compound (small, organic) 6

synthesis of compound ↓ manipulation of structure to get better drug (greater efficacy, fewer side effects) Aspirin 7

Modern Drug Discovery Process Drug discovery process begins with a disease (rather than a treatment) Use disease model to pinpoint relevant genetic/biological components (i.e. possible drug targets) If little known about the disease  test procedures usually depend on animal models.

Modern Drug Discovery Process disease → genetic/biological target ↓ discovery of a “lead” molecule - design assay to measure function of target - use assay to look for modulators of target’s function ↓ high throughput screen (HTS) - to identify “hits” (compounds with binding in low nM to low μ M range)

Modern Drug Discovery Process small molecule hits ↓ manipulate structure to increase potency ↓ optimization of lead molecule into candidate drug fulfillment of required pharmacological properties: potency, absorption, bioavailability, metabolism, safety ↓ clinical trials

Interesting facts Over 90% of drugs entering clinical trials fail to make it to market The average cost to bring a new drug to market is estimated at $770 million

Impact of Structural Bioinformatics on Drug Discovery Speeds up key steps in DD process by combining aspects of bioinformatics, structural biology, and structure-based drug design

human genome polysaccharideslipids nucleic acids proteins proteins withbinding site “druggable genome” = subset of genes which express proteins capable of binding small drug-like molecules