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Lecture info Meeting place: NSI 2144 Meeting times: Tue 4:00-4:50pm

Bio Sci 2B Computer Aided Drug Design

What is a drug? Defined composition with a pharmacological effect Regulated by the Food and Drug Administration (FDA) What is the process of Drug Discovery and Development?

Drugs and the Discovery Process Small Organic Molecules –Natural products fermentation broths plant extracts animal fluids (e.g., snake venoms) –Synthetic Medicinal Chemicals Project medicinal chemistry derived Combinatorial chemistry derived Biological Molecules –Natural products (isolation) –Recombinant products

Discovery vs. Development Discovery includes: Concept, mechanism, assay, screening, hit identification, lead demonstration, lead optimization Discovery also includes In Vivo proof of concept in animals and demonstration of a therapeutic effect Development begins when the decision is made to put a molecule into phase I clinical trials

Discovery and Development The time from conception to approval of a new drug is typically years The vast majority of molecules fail along the way The estimated cost to bring to market a successful drug is now $800 million!! (Dimasi, 2000) However, the annual profit of a drug can be $ 1 billion per year Pharmaceutical industry has been one of the best performing sections in economy

Drug Discovery Disciplines Medicine Physiology/pathology Pharmacology Molecular/cellular biology Automation/robotics Medicinal, analytical,and combinatorial chemistry Structural and computational chemistries Computational biology

Drug Discovery Program Rationales Unmet Medical Need Me Too! - Market - ($$$s) Drugs in search of indications –Side-effects often lead to new indications Indications in search of drugs –Mechanism based, hypothesis driven, reductionism

Issues in Drug Discovery Hits and Leads - Is it a “Druggable” target? Resistance Delivery - oral and otherwise Metabolism Solubility, toxicity Patentability …

A Little History of Computer Aided Drug Design 1960’s - Review target-drug interactions 1980’s- Automation - high throughput target/drug selection 1980’s- Databases (information technology) - combinatorial libraries 1980’s- Fast computers - docking 1990’s- Faster computers - genome assembly - genomic based target selection 2000’s- Fast information handling - pharmacogenomics

From the Computer Perspective

Comparing Growth Rates

From the Target Perspective

(a) myoglobin (b) hemoglobin (c) lysozyme (d) transfer RNA (e) antibodies (f) viruses (g) actin (h) the nucleosome (i) myosin (j) ribosome Status - Numbers and Complexity Courtesy of David Goodsell, TSRI

From the Drug Perspective

Combinatorial Libraries Blaney and Martin - Curr. Op. In Chem. Biol. (1997) 1:54-59 Thousands of variations to a fixed template Good libraries span large areas of chemical and conformational space - molecular diversity Diversity in - steric, electrostatic, hydrophobic interactions... Desire to be as broad as “Merck” compounds from random screening Computer aided library design is in its infancy

Computer-Assisted Drug Design Computer driven drug discovery Data driven drug discovery

An overview of biomolecules Living organisms are more ordered than their surroundings. So the first task is to maintain a separation between inside and outside. The second task is to spend energy to keep things in order. The functions of life are to facilitate the acquisition and expenditure of energy.

Cell Cells are the smallest compartments that are ordered and separated from the surroundings. Note that ordered compartments were difficult to get started de novo, and so have found ways to pass on the apparatus necessary to perpetuate themselves.

Tasks of a living cell Gather energy from surroundings. Use energy to maintain inside/outside distinction. Use extra energy to reproduce. Develop strategies for being efficient at their tasks: developing ways to move around; developing signaling capabilities; developing ways for energy capture; developing ways of reproduction.

Molecular means to realize these tasks Ability to separate inside from outside with lipids Ability to build three-dimensional molecules that assist their functions, proteins, RNA Ability to store information for these tasks, part of reproduction also, DNA

A simple model of a cell proteinsLipid membraneDNA

Lipids Made of hydrophilic (water loving) molecular fragment connected to hydrophobic fragment. Spontaneously form sheets (lipid bilayers, membranes) in which all the hydrophilic ends align on the outside, and hydrophobic ends align on the inside. Creates a very stable separation, not easy to pass through except for water and a few other small atoms/molecules.

Lipids

Lipid bilayers: Structure

Lipid bilayers: Functions

Lipid bilayers

A simple model of a cell proteinsLipid membraneDNA

Proteins: A chain of linked subunits These subunits are amino acids (also called protein residues for historical reasons). There are 20 different amino acids with different physical and chemical properties. The interaction of these properties allows a chain of the amino acids (upto 1000’s long) to fold into a unique, reproducible 3D shape.

20 amino acids Common back bone Unique side chain Ala A Alanine Glu E Glutamic Acid Arg R Arginine

Amino acid structures Fig. 5.3

Amino acid properties Polar amino acids: THR, SER, ASN, GLN, TYR, HIS, TRP, CYS Charged amino acids: ASP, GLU, LYS, ARG, HIS, CYS Hydrophobic amino acids: VAL, LEU, ILE, PHE, ALA, PRO, GLY, MET, TYR, TRP

Representations of proteins 1-d sequence: Alanine-Tyrosine-Valine= ALA-TYR-VAL= A-Y-V

Representations of proteins: 2-d THH HHHHHTLLLH HHHHHGGGLS STTEEEEEEE

Representations of proteins: 3-d

Protein features Protein can be stabilized by salt bridges Protein can be folded to a unique structure due to the existence of disulfide bonds Protein may function as an enzyme whose active sites are crucial for its function

A simple model of a cell proteinsLipid membraneDNA

DNA structures DNA packs in the nucleus to form chromosome

DNA structure

DNA is a sequence too It has a common back bone, and side chains, though only 4 kinds. A sequence of these subunits is also specified as a string: ACTTAGGACATTTTAG, which is a simplified representation of a chemical structure.

DNA is a sequence too DNA uses an alphabet of 4 letters (ATCG), i.e. bases. Long sequences of these 4 letters are linked together to create genes and control information.

Information in DNA DNA encodes proteins: each amino acid can be specified by 3 bases. Ribosome reads a DNA sequence and creates the corresponding protein chain. GENETIC CODE: 64 mappings of 3 bases to 1 amino acid.

Genetic code

The gene for myoglobin ctgcagataa ctaactaaag gagaacaaca acaatggttc tgtctgaagg tgaatggcag ctggttctgc atgtttgggc taaagttgaa gctgacgtcg ctggtcatgg tcaggacatc ttgattcgac tgttcaaatc tcatccggaa actctggaaa aattcgatcg tttcaaacat ctgaaaactg aagctgaaat gaaagcttct gaagatctga aaaaacatgg tgttaccgtg ttaactgccc taggtgctat ccttaagaaa aaagggcatc atgaagctga gctcaaaccg cttgcgcaat cgcatgctac taaacataag atcccgatca aatacctgga attcatctct gaagcgatca tccatgttct gcattctaga catccaggta acttcggtgc tgacgctcag ggtgctatga acaaagctct cgagctgttc cgtaaagata tcgctgctaa ctgggttacc agggttaatg aggtacc BASE COUNT 155 a 108 c 115 g 129 t MVLSEGEWQLVLHVWAKVEADVAGHGQDILIRLFKSHPETLEKFDRFKHLKTEAEM KASEDLKKHGVTVLTALGAILKKKGHHEAELKPLAQSHATKHKIPIKYLEFISEAI IHVLHSRHPGNFGADAQGAMNKALELFRKDIAAKYKELGYQG

Genes and control The set of all genes required for an organism is the organism’s GENOME. Human genome has 3,000,000,000 bases divided into 23 linear segments (chromosomes). A gene has on average 1340 DNA bases, thus specifying a protein of about 447 amino acids. Humans have about 35,000 genes = 40,000,000 DNA bases = 3% of total DNA in genome. Humans have another 2,960,000,000 bases for control information. (e.g. when, where, how long, etc...)

Genotype and phenotype Genotype—the genetic sequences associated with an individual organism. Phenotype—the observable non-sequence features of an individual organism (e.g. color, shape, activity of an enzyme)

How do we proceed? In order to obtain insight into the ways in which genes and gene products function: Analyze DNA and protein sequences to search clues for structure, function and control – sequence analysis Analyze structures to search clues for sequences, function and control – structural analysis Understand how sequences and structures leads to functions – functional analysis

But what are functions of genes? Signal transduction: sensing a physical signal and turning into a chemical signal Structural support: creating the shape and of a cell or set of cells Enzymatic catalysis: accelerating chemical reactions otherwise too slow to be useful for living things Transport: getting things in and out of a compartment.

But what are functions of genes? Movement: contracting in order to pull things together or push things apart Transcription control: deciding when other genes should be turned on/off Trafficking: affecting where different elements end up inside a cell.

Evolution is the key Common descent of organisms implies that they will share many basic approaches Development of new phenotypes in response to environmental pressure can lead to specialized approaches More recent divergence implies more shared approaches between species The important thing is which is shared and which is not unshared. This is also important for drug discovery in biomedicine.

Seeing is believing: Computer Graphics

Je-2147/HIV Protease Complex

HIV Integrase

The Small Ribosomal Subunit

The Large Ribosomal Subunit