UCSD Deans and Chairs Presentation - PDB & Drug Discovery

The RCSB Protein Data Bank

www.rcsb.org

Phil BourneSSPPS

[email protected]

1/25/11 UCSD Deans and Chairs Meeting

Agenda

What is the RCSB PDB and what does it bring to SSPPS/UCSD?

Examples of how it is being used in drug discovery

How SSPPS/UCSD might leverage it going forward

1/25/11 UCSD Deans and Chairs Meeting

What is the Protein Data Bank (PDB)?

The single community owned worldwide repository on the structures of publically accessible biological macromolecules

A resource used by ~ 200,000 individuals per month

A resource distributing equivalent to ¼ the National Library of Congress each month

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Nu

mb

er o

f re

leas

ed e

ntr

ies

Year

Total Contents by Year

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Depositor locations

Download locations

RCSB PDB

PDBe

PDBj

Depositions since 2000

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Cooperative Community Action

Individual letters to editors of journals

Committees IUCr commission on

Biological Macromolecules ACA/USNCCr Richards committee

Funding agencies Articles in journals

Marvin Cassman Fred Richards Richard Dickerson

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46157

1301

1093

755

39

582655

Structure distribution

Other

Protein only

Protein-DNA complexes

DNA only

Protein-RNA complexesRNA only

RNA-DNA hybrid

Resolution distribution:

protein structures

Resolution distribution:

other structures

Year

Res

olu

tion

Resolution distribution: all structures

Structure determination

methods

Num

ber

of

stru

ctu

res

Year

What has the PDB enabled?

Safe storage and retrieval of macromolecular structure data

Increased understanding of sequence-structure-function relationships:

– A “parts list” for structure modeling and prediction– Structure based drug design– Protein structure classification– The details in large scale interactions

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Lysozyme: Lessons learned

Blake, Koenig, Mair, North, Phillips, Sarma (1965) Nature 206: 757.

T4 bacteriophage (459 structures) Amino acid replacement studies

suggest that fraction of amino acid residues that define the structure of T4 lysozyme is about 50% B.W. Matthews (1996) FASEB J.10: 35-41.

Insight into folding and catalysis

Hen egg white (297 structures) Low sequence identity Structural similarity of active site

to T4B.W. Matthews, M.G. Remington, M.G. Grutter, W.F. Anderson (1981) J.Mol.Biol. 147: 545-58.

Insight into evolution and catalysis1/25/11 UCSD Deans and Chairs Meeting

Myoglobin and hemoglobin: Lessons learned

Lodish et al.6

Whale myoglobin (185 structures) Different ligands: oxygen, carbon dioxide1

Amino acid substitution studies2

Laue studies3

Insight into function and dynamics

Other species myoglobin Low sequence identity, same structure4

Insight into evolution

Human hemoglobin (178 structures)

Insight into function and disease (sickle cell anemia, thalassemia)5

Other species hemoglobin Low sequence identity, same structure4

Profound insight into evolution1Kuriyan, Wilz, Karplus, Petsko (1986) J. Mol. Biol. 192:133–154; 2Quillin, Arduini, Olson, Phillips, Jr. (1993) J. Mol. Biol. 234: 140–155, Carver, Brantley Jr, Singleton, Arduini, Quillin, Phillips Jr, Olson (1992) J. Biol. Chem. 267:14443–14450; 3Bourgeois, Vallone, Schotte, Arcovito, Miele, Sciara, Wulff, Anfinrud, Brunori (2003) PNAS 100: 8704-8709; 4Dickerson, Geis (1983) Hemoglobin: structure, function, and pathology; 5Kidd, Baker, Mathews, Brittain Baker (2001) Prot. Sci. 10:1739-1749, Harrington, Adachi, Royer Jr. (1998) J. Biol. Chem. 273: 32690 - 32696; 6Lodish, Berk, Zipursky, Matsudaira, Balitmore, Darnell (2000) Molecular Cell Biology WH Freeman & Co.

Agenda

What is the PDB and what does it bring to UCSD?

Examples of how it is being used in drug discovery

How UCSD might leverage it going forward

1/25/11 UCSD Deans and Chairs Meeting

RCSB PDB Pharmacology/Drug View

Establish linkages to drug resources (FDA, PubChem, DrugBank, ChEBI, BindingDB etc.)

Create query capabilities for drug information

Provide superposed views of ligand binding sites

Analyze and display protein-ligand interactions

Drug Name Asp

Aspirin

Has Bound Drug% Similarity to Drug Molecule 100

Mockups of drug view features

HIV-related structures

311

110

39

27

122

Year

Protease

Reverse Transcriptase

Gag protein

Integrase

Other

HIV-1 reverse transcriptase

Amprenavir (GSK) Fosamprenavir (GSK)

Lopinavir (Abbott) Atazanavir (BMS)

Nelfinavir (Agouron) Darunavir (Tibotec)

Tipranavir (BI) Indinavir (Merck)

Ritonavir (Abbott) Saquinavir (Roche)

2R5P, 2B7Z, 2AVV, 2AVO, 2AVS, 1SGU, 1SDT, 1SDV, 1SDU, 1K6C, 1C6Y, 2BPX, 1HSG, 1HSH

1T7J, 1HPV

2B60, 1RL8, 1SH9, 1N49, 1HXW

2QAK, 2PYM, 2Q63, 2PYN, 2Q64, 2R5Q, 1OHR

2O4N, 2O4L, 2O4P, 1D4Y, 1D4S

3D1X, 3D1Y, 3CYX, 2NMW, 2NMZ, 2NNP, 2NMY, 2NNK, 1C6Z, 1FB7

2FXE, 2FXD, 2O4K, 2AQU, 2FND 2RKG, 2RKF,

2QHC, 2Z54, 2Q5K, 2O4S, 1RV7, 1MUI

Abacavir (GSK)

Nevirapine (BI) Stavudin (BMS)

Efavirenz (BMS) Lamivudine (GSK)

Zidovudine (GSK) Emtricitabine (Gilead)

Tenofovir (Gilead) Zalcitabine (Hoffmann- LaRoche)

Etravirine (Tibotec) Delavirdine (Pfizer)

2HND, 2HNY, 1S1U, 1S1X, 1LW0, 1LWE, 1LWC, 1LWF, 1JLB, 1JLF, 1FKP, 1VRT, 3HVT

1JKH, 1IKW, 1IKV, 1FKO, 1FK9

1S6P

1T05

HIV-1 protease

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Worldwide Protein Data Bank

www.wwpdb.org

Consider one example of using the corpus as a whole from our own research – high throughput hypothesis generation for use in drug discovery

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Polypharmacology - One Drug Binds to Multiple Targets

• Tykerb – Breast cancer

• Gleevac – Leukemia, GI cancers

• Nexavar – Kidney and liver cancer

• Staurosporine – natural product – alkaloid – uses many e.g., antifungal antihypertensive

Collins and Workman 2006 Nature Chemical Biology 2 689-700

The TB-Drugome

1. Determine the TB structural proteome

2. Determine all known drug binding sites from the PDB

3. Determine which of the sites found in 2 exist in 1

4. Call the result the TB-drugome

Kinnings et al 2010 PLoS Comp Biol 6(11): e1000976

UCSD Deans and Chairs Meeting

1. Determine the TB Structural Proteome

284

1, 446

3, 996 2, 266

TB proteome

homology

models

solve

d

structu

res

High quality homology models from ModBase (http://modbase.compbio.ucsf.edu) increase structural coverage from 7.1% to 43.3%

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2. Determine all Known Drug Binding Sites in the PDB

Searched the PDB for protein crystal structures bound with FDA-approved drugs

268 drugs bound in a total of 931 binding sites

No. of drug binding sites

MethotrexateChenodiol

AlitretinoinConjugated estrogens

DarunavirAcarbose

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Map 2 onto 1 – The TB-Drugomehttp://funsite.sdsc.edu/drugome/TB/

Similarities between the binding sites of M.tb proteins (blue), and binding sites containing approved drugs (red).

From a Drug Repositioning Perspective

Similarities between drug binding sites and TB proteins are found for 61/268 drugs

41 of these drugs could potentially inhibit more than one TB protein

No. of potential TB targets

raloxifenealitretinoin

conjugated estrogens &methotrexate

ritonavir

testosteronelevothyroxine

chenodiol

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Top 5 Most Highly Connected Drugs

Drug Intended targets Indications No. of connections TB proteins

levothyroxine transthyretin, thyroid hormone receptor α & β-1, thyroxine-binding globulin, mu-crystallin homolog, serum albumin

hypothyroidism, goiter, chronic lymphocytic thyroiditis, myxedema coma, stupor

14

adenylyl cyclase, argR, bioD, CRP/FNR trans. reg., ethR, glbN, glbO, kasB, lrpA, nusA, prrA, secA1, thyX, trans. reg. protein

alitretinoin retinoic acid receptor RXR-α, β & γ, retinoic acid receptor α, β & γ-1&2, cellular retinoic acid-binding protein 1&2

cutaneous lesions in patients with Kaposi's sarcoma 13

adenylyl cyclase, aroG, bioD, bpoC, CRP/FNR trans. reg., cyp125, embR, glbN, inhA, lppX, nusA, pknE, purN

conjugated estrogens estrogen receptor

menopausal vasomotor symptoms, osteoporosis, hypoestrogenism, primary ovarian failure

10

acetylglutamate kinase, adenylyl cyclase, bphD, CRP/FNR trans. reg., cyp121, cysM, inhA, mscL, pknB, sigC

methotrexatedihydrofolate reductase, serum albumin

gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, severe psoriasis, rheumatoid arthritis

10

acetylglutamate kinase, aroF, cmaA2, CRP/FNR trans. reg., cyp121, cyp51, lpd, mmaA4, panC, usp

raloxifeneestrogen receptor, estrogen receptor β

osteoporosis in post-menopausal women 9

adenylyl cyclase, CRP/FNR trans. reg., deoD, inhA, pknB, pknE, Rv1347c, secA1, sigC

Agenda

What is the PDB and what does it bring to UCSD?

Examples of how it is being used in drug discovery

How UCSD might leverage it going forward

1/25/11 UCSD Deans and Chairs Meeting

How UCSD Might Leverage the PDB

Part of the foundation of a drug discovery effort.

Outreach tool The Devil is in the Details - talented group of

PDB scientists capable of working with the details

Lots of experience with UCSD’s unique infrastructure, data curation, management, dissemination etc. available for new initiatives

1/25/11 UCSD Deans and Chairs Meeting

Acknowledgements

Funding Agencies: NSF, NIGMS, DOE, NLM, NCI, NCRR, NIBIB, NINDS, NIDDK

241/25/11 UCSD Deans and Chairs Meeting