Physicochemical properties in drug design

School of Pharmacy

University of East Anglia

Norwich NR4 7TJ, United Kingdom

a.ganesan@uea.ac.uk

XXI Escola de Verao em Quimica

Farmaceutica e Medicinal

Rio de Janeiro, 29 Janeiro 2015

Ganesan

UEA and Norwich

School of Pharmacy at UEA

• Ranked #1 in the UK in the National Student Survey and #1

for quality of research publications.

• Intake of 135 undergraduate students per year.

• MPharm course- four year degree followed by one year

preregistration training and GPhC examination.

• Department is divided into four sections:

• Medicinal Chemistry

•Drug Delivery and Pharmaceutical Materials

•Pharmaceutical Cell Biology

•Medicines Management

Research interests

O

O

O

NH

NH

NH

O

S

S

HO

O

SMe

thailandepsin A

class I selective HDAC inhibitor

Org. Lett. 2011, 13, 6334

Epigenetics

PRSFLV peptide

reversible LSD1 inhibitor

ACS Chem. Biol. 2013, 8, 1677

Calcium signalling

O

N

N

F

NH

NH

O

OH

Ned-19

NAADP receptor antagonist

Nature Chem. Biol. 2009, 5, 220

Natural products

R1 NH2

OTi(OEt)4

R2 CHO

CH2Cl2R1 N

H

O

R2

OEt

19 examples35-99%

Synthetic methodology

N-acyl aminal synthesis

Org. Lett. 2014, 16, 10

NH

HN

NH

HN

O

O

O

OHN

O

ONH

O

HN

O

O

OH

HO

kahalalide A

antimycobacterial

J. Med. Chem. 2005, 48, 1530

HNHN

N

HNO

OH

OH

H

okaramine J

antiinsecticidal

Org. Lett. 2003, 5, 2825

Types of drugs

• Herbal medicines and extracts

– Preparations containing a mixture of components.

– Active ingredients may be unknown.

– Issues with regulation, standardisation, impurities.

– Potential for drug-drug interactions.

– Standard of care for ~80% of world population.

– Usually administered orally.

• Small molecules

– Compounds with MW ≤ 750.

– Made by chemists or natural products purified from extracts.

– Often administered orally.

• Biologics

– Macromolecules such as proteins.

– Made by biologists by cell culture, manufacture is expensive.

– Examples include recombinant proteins and antibodies.

– Usually administered intravenously.

Examples of drugs

Herbal extract

• Senna, dried leaves of Senna

alexandrina

• Used traditionally for millennia

• Active principle- senna

glycosides, laxative

• Treatment of constipation

Small molecule

• sildenafil (Viagra), MW 475

• Launced in 1998 by Pfizer

• PDE-5 enzyme inhibitor

• Treatment of erectile

dysfunction and hypertension

Biologic

• trastumuzab (Herceptin), MW ~

148,000

• Launced in 1998 by Genentech

• Monoclonal antibody against

HER2/neu receptor

• Treatment of breast cancer,

~$70,000 for a full course

Top 10 best-selling drugs 2013

Drug API Manufacturer Indication $ Sales in

billions

Humira adalimumab AbbVie arthritis 11.0

Enbrel etanercept Amgen arthritis 8.8

Remicade infliximab Johnson & Johnson arthritis 8.4

Advair fluticasone/

salmeterol

GlaxoSmithKline asthma 8.3

Lantus insulin Sanofi diabetes 7.6

Rituxan rituximab Roche cancer 7.5

Avast bevacizumab Roche cancer 6.8

Herceptin trastuzumab Roche cancer 6.7

Crestor rosuvastatin AstraZeneca high cholesterol 6.0

Abilify aripiprazole Bristol-Myers Squibb antipsychotic 5.5

bold = biologics

italics = small molecules

Source: FiercePharma

Risk versus reward in drug discovery

p(TS): probability of successful transition from one stage to the next

WIP: work in process needed to achieve one NME

NME: new molecular entity

How to improve R&D productivity: the pharmaceutical industry's grand challenge

Steven M. Paul, Daniel S. Mytelka, Christopher T. Dunwiddie, Charles C. Persinger,

Bernard H. Munos, Stacy R. Lindborg & Aaron L. Schacht

Nature Reviews Drug Discovery 9, 203-214

Why do drugs fail?

Efficacy

Target validation

Toxicity

On-target effects

Toxicity

Off-target effects

Efficacy

Poor PK

Economic

Profitability

Toxicity

Toxicophores

The target does not

have a significant

effect on the disease.

The drug does not

reach the

concentration

necessary to have a

therapeutic effect on

the disease.

The drug may be safe

and effective but not

sufficiently profitable.

The drug has

structural features

that cause toxicity.

The toxicity is due to

the intended

mechanism of action

and an extension of

the therapeutic

effect.

The toxicity is

unrelated to the

therapeutic effect.

Failure in drug discovery

Failing early is more efficient in terms of time and money.

Important to use experience learned from past successes and failures in drug

discovery.

Every drug discovery project is different.

Failure in drug discovery- AstraZeneca analysis

Predicting success in drug discovery- AstraZeneca analysis

D. Cook, D. Brown, R. Alexander,

R. March, P. Morgan, G.

Satterthwaite, M. N. Pangalos

Nature Rev. Drug Discovery 13,

419–431 (2014)

AstraZeneca’s 5R model for drug discovery

Accelerating early stage drug discovery

• Combinatorial chemistry- rapid synthesis of large numbers of compounds.

• Integrated with high-throughput screening to identify leads for drug

discovery, popular in the 1990s.

• Possible to synthesize >1,000 compounds/week and screen >1,000

compounds/day.

• How do we decide which compounds to make?

Examples of successful drugs

Successful drug molecules come in a diverse variety of shapes and sizes.

To identify common trends, statistical analysis of large numbers is needed.

lithium cation

depression

metformin

diabetes paracetamol

analgesic

itraconazole

antifungal

taxol

cancer

Li+

Guidelines for druglike matter

Statistical analysis of successful drug molecules to identify common features.

Generate guidelines for predicting druglikenes and oral bioavailability.

The most widely used metrics:

Lipinski‟s Rule of Five

Number of rotatable bonds

Total polar surface area

Fraction of sp3 hybridised carbons

Oral absorption

Oral administration of drugs preferred for convenience and patient compliance.

Absorption of oral drugs

•Oral absorption is affected by a number of drug parameters.

•Aqueous solubility

•Lipophilicity

•Size

•Presence of ionisable functional groups, H bonding- drugs with a pKa of 6-8 are

~50% ionized at blood pH of 7.4

•Susceptibility to gut wall metabolism

Absorption in the small intestine takes place by three major mechanisms:

1. Passive diffusion from intestine into cells in the gut and then diffusion out of the

cell out of the gut wall. Driven by a concentration gradient and requires drug to

be sufficiently hydrophobic to pass through the cell membrane.

2. Active transport mediated by transmembrane transporters with the expenditure

of energy. Can involve both influx and efflux.

3. Interstitial delivery through spaces between cells, mainly for polar compounds

with MW < 200.

Lipinski’s Rule of Five •Lipinski „Rule of Five‟- rules for oral absorption by Chris Lipinski at Pfizer.

•Based on statistical analysis of drugs reaching Phase II clinical trials, 90% of which

follow these rules.

•Macromolecular drugs e.g. peptides and nucleotides excluded from data set.

•There are four rules, each with a limit of 5 or a multiple of 5.

•clog P ≤ 5

•MW ≤ 500

•H bond donors ≤ 5

Estimated by counting OH and NH functional groups.

•H bond acceptors ≤10

Estimated by counting total N + O.

•The rules are based on passive oral absorption in humans.

• Many oral drugs do not obey all four of the rules. For some indications e.g. CNS and

antimicrobials, the numbers need to be modified.

Basis for Lipinski’s rules

•Clog P ≤ 5

•Lipophilic compounds have poor aqueous solubility. They may be insoluble, or too

highly bound to plasma proteins, or in lipid bilayers.

•Lipophilic compounds tend to be metabolised, leading to poor availability.

•Typically, drugs have logP 1.5-3. If log P is too low, compounds may not be

transported by passive diffusion through the cell membrane.

•Molecular weight ≤ 500

•As molecular weight increases, likelihood of large number of functional groups e.g. N,

O, NH, OH.

•These functional groups are solvated, leading to prohibitive energy cost for their

desolvation.

•As molecular weight increases, likelihood for more sites of drug metabolism and

breakdown.

•H bond donors and acceptors

•H bond donors and acceptors are likely to be solvated with bulk water.

•There is an expenditure of energy to desolvate the drug before it can be absorbed

through the gut cell wall.

•H bond donors have a higher energy cost than acceptors, hence less permitted than

H bond acceptors.

N O O

H H

HO

HOH H

Drug in Gut

- n H2ON O O

H H

Drug in GutCell Membrane

Basis for Lipinski’s Rules

Examples of the importance of log P N

O

O

O

O

cocaine

O

O

N

simplifiedsyntheticl analogue

C17H21NO4Mol. Wt.: 303

H bond donors- noneH bond acceptors (N + O)- 5

Clog P 2.6

C13H19NO2Mol. Wt.: 221

H bond donors- noneH bond acceptors (N + O)-3

Clog P 3.3higher than cocaine

O

O

N

procaine (Novocaine)local anaesthetic

NH2

C13H20N2O2Mol. Wt.: 236

H bond donors- oneH bond acceptors (N + O) - 4

Clog P 2.5similar to cocaine

Cl

Cl

ON

S

N

Cl

C16H13Cl3N2OSMol. Wt.: 388

H bond donors- noneH bond acceptors (N + O)- 3

Clog P 4.8topical use, not oral

tioconazole

F

F

NN

N

NN

N

OH

C13H12F2N6OMol. Wt.: 306

H bond donors- oneH bond acceptors (N + O)- 7

Clog P -0.4orally bioavailable antifungal

fluconazole

Additional guidelines for oral bioavailability

•Number of rotatable bonds ≤ 10

Ten or fewer for good oral bioavailability.

Rigidity locks drug into the preferred

conformation for binding to the

target.

Flexibility can lead to binding to other

proteins and side effects.

•Total polar surface area ≤ 140 A2

Higher values lead to

compounds that are too hydrophilic.

GlaxoSmithKline analysis of >1100 compounds:

Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.;

Smith, B. R.; Ward, K. W.; Kopple, K. D.

J. Med. Chem. 2002, 45, 2615-2623.

Additional guidelines for oral bioavailability

•Fraction of sp3 carbon (Fsp3)

Number of sp3 hybridized carbons divided by total number of carbons.

Drug candidates typically have Fsp3 > 0.4.

•Aromatic versus sp3 carbon (Ar - sp3)

Number of aromatic carbon atoms minus sp3 hybdridised carbons.

Typically ≤ 18 for drug molecules.

Measures of compound „flatness‟, correlate with issues in solubiliity and metabolism.

Ritchie, T. J.; Macdonald, S. J. F. J. Med. Chem. 2014, 57, 7206-7215.

GSK 4/400 rule

Gleeson, M. P. J. Med. Chem. 2008, 51, 817

GSK 4/400 and developability

Ritchie, T. J.; Macdonald, S.

J. F.; Peace, S.; Pickett, S. D.;

Luscombe, C. N.

Med. Chem. Commun. 2013,

4, 673-680.

Natural Products and Drug Discovery

•Crude natural product extracts as drugs.

•Pure natural products as drugs.

•Semisynthetic natural products as drugs.

•Natural products as starting materials.

•Natural products as leads for synthetic drugs.

•Natural products as biological probes.

Six pathways from the poppy plant

Why are natural products special?

• Natural products often occupy complementary chemical

space compared to synthetic compounds.

• Natural products are often bioavailable (even oral) despite

violating physicochemical properties predicted for druglike

molecules.

overview of natural products

• Ortholand, J.-Y.; Ganesan, A. Curr. Opin. Chem. Biol. 2004, 8, 271-280.

• Ganesan, A. Curr. Opin. Biotechnol. 2004, 15, 584-590.

• Ganesan, A. In Boldi, A. M. (ed.) Combinatorial Synthesis of Natural

Product-Based Libraries, CRC, Boca Raton, 2006, 37-52.

natural product drug physicochemical properties

• Ganesan, A. Curr. Opin. Chem. Biol. 2008, 12, 306-317.

• Ganesan, A. In Natural Products and Cancer Drug Discovery; Koehn, F.

E. Ed.; Springer: Heidelberg, 2012, 3-15.

The chemical space of biosynthesis

•Very small number of building blocks.

•Very large number of branch points leading to diverse scaffolds.

•Aqueous chemistry at ambient temperature.

•Regioselective chemistry without the need of protecting groups.

•Chemistry dominated by oxygen and oxidative reactions.

•Widespread occurrence of C-H activation and stereochemical features.

Natural products and synthetic drugs are divergent in

chemical space, but converge in biological space

Descriptor The ‘average’

synthetic drug

The ‘average’

natural product

Composition C17N2O4S0.2X 0.3 C23N1O6

MW 340 414

Slog P 2 2

H-bond acceptors 6 7

H-bond donors 2 3

Rotatable bonds 6 4

Rings 3 4

Chiral centres 2 6

New Chemical Entities, 1981-2006, by source (N = 1184).

“B": Biological.

"N": Natural product.

"ND": Derived from a natural product and is usually a semisynthetic modification.

“NM”: Natural product mimic.

"S": Totally synthetic drug.

"S*": Made by total synthesis, but the pharmacophore is from a natural product.

"V": Vaccine.

Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461-477.

The impact of natural products on drug discovery

Drugs from natural products 1970-2006

NH

OH

HO

OH

OH

OH

O

OH

OH

O

OH

OH

OH

HO

validamycinStreptomyces hygroscopicus-glucosidase (intracellular)

OO

O O

O

OH

O

O

NMe2

O

O

OH

O

O

HOCHO

midecamycinStreptomyces mycarofaciens50S ribosome (intracellular)

O O

OCO2H

OH

HOOOH

H H

pseudomonic acidPseudomonas fluorescensIle t-RNA synthetase (intracellular)

OO

HO

H

OO

O O

O

O

OHO

NH

O

O

taxolTaxus brevifoliatubulin (intracellular)

N

S

O

HN

OMe

CO2H

OO

NH2HO2C

NH2

cephamycin CStreptomyces clavuligeruspenicillin-binding proteins (cell wall)

O

HO OH

NHO

N

HN

N

OH

coformycinStreptomyces kaniharaensisadenosine deaminase (intracellular)

HNOH

OH

HN

O

ON

O

NH

OHO

OH

HO

HN

O

HO

N

NH

O

HO

OH

echinocandin BAspergillus nidulans-1,3-D-glucan synthase (cell wall)

O

HO OH

NHO

N

H2N

HO

O

mizoribineEupenicillium brefeldianuminosine monophosphate dehydrogenase(intracelllular)

NO

O

O

O

O

OH

OMe

O

O

OMe

rapamycinStreptomyces hygroscopicusmammalian target of rapamycin(intracellular)

OH

OMe

O

OH

O O

O

H

O

OHO

compactinPenicillium citrinumHMG CoA reductase(intracellular)

N

O

N

NH

O

O

N

O

NH O

HN O

NO

HN

OOH

N

O

N

ON

O

H

cyclosporine ATolypocladium inflatumcalcineurin (intracellular)

O

O

O

O

HNCHO

lipstatinStreptomyces toxytricinipancreatic lipase (extracellular)

HO2CHN

O

OH

NH2

bestatinStreptomyces olivoreticuliaminopeptidase (intracellular)

O OO

OO

H

H

H

artemisininArtemisia annuaP. falciparumoxidative damage(intracellular)

O

H

OH

OH

O

OOH

O

forskolinColeus forskohliiadenylyl cyclase(cell membrane)

OH

OHplaunotolCroton sublyratusH. pylori (cell membrane)

NO S

O O

OH

OMeHN

O

SQ26,180Chromobacterium violaceumpenicillin binding proteins(cell wall)

O

O

HOH

OO

O

OO

H

OH

MeO

OO

HO

OMe

avermectin B1aStreptomyces avermitilisGlu-gated chloride channel (cell membrane)

NO

CO2H

OHH H

S

NH2

thienamycinStreptomyces cattleyapenicillin binding proteins(cell wall)

H2N NH

NH

HN

NH

NH OH O OH

OspergualinBacillus laterosporusT-cell maturation (intracellular)

H2NO

O

OH

H

H

arglabinArtemisia glutinosafarnesyl transferase(cell membrane)

O

OH O

O

N O

O

O

HOOMe

H

H

OMe

MeO

HO

FK506Streptomyces tsukubaensiscalcineurin (intracellular)

O

HN

HN

HO2C

O

HNO

HO2C NH

O

HN

H2N

O

NH

O

HN

O

NH

HO

O

HN

HO2C

O

O

O

NH

O

H2N

O

NHHO2C

O

HN O

NH

O

CONH2

HNdaptomycinStreptomyces roseosporusGram positive bacteria (cell membrane)

O

OH

S

MeSS

HN

MeO2C

O

O

O O

OH

HN

OMe

NH

O

OS

OH

O

I

OMe

OMe

O

O

OMe

OH

OH

calicheamicin1

Micromonospora echinospora

DNA damage (intracellular)

HO

The Lipinski Universe of successful natural products

NP Formula MW ClogP Hdon Hacc Rot PSA HA

cephamycin C C16H21N3O9S 431 -4.3 4 10 11 186 29

artemisinin C15H22O5 282 3.0 0 5 0 54 20

thienamycin C11H16N2O4S 272 -0.9 3 5 5 104 18

SQ26180 C6H10N2O6S 238 -2.2 2 6 3 113 15

coformycin C11H16N4O5 284 -1.9 5 9 2 132 20

arglabin C15H18O3 246 1.4 0 3 0 39 18

mizoribine C9H13N3O6 259 -1.4 5 8 3 151 18

compactin C23H34O5 391 4.0 1 5 7 73 28

bestatin C16H24N2O4 308 -0.9 4 5 8 113 22

forskolin C22H34O7 411 1.4 3 7 3 113 29

plaunotol C20H34O2 307 2.8 2 2 11 41 22

spergualin C17H37N7O4 404 -1.4 7 9 18 190 28

Average C15H23N2O5 319 0 3 6 6 109 22

Cutoffs: MW 500, Clog P 5, Hdon 5, Hacc 10, Rot 10, PSA 140, HA 30

The Anti-Lipinski Universe of

successful natural products

NP Formula

MW ClogP Hdon Hacc Rot PSA HA

midecamycin C41H67NO15 814 2.1 3 16 14 206 57

pseudomonic acid C26H44O9 501 2.5 4 9 17 146 35

echinocandin B C52H81N7O16 1060 1.8 14 16 20 368 75

avermectin B1a C48H74O14 875 2.8 3 14 8 170 62

daptomycin C72H101N17O26 1621 -3.7 22 29 35 702 115

taxol C47H51NO14 854 3.0 4 14 14 221 62

calicheamicin C55H74IN3O21S4 1368 3.2 8 23 24 308 84

validamycin C20H35NO13 498 -5.2 12 14 7 253 34

rapamycin C51H79NO13 914 4.3 3 13 6 195 65

cyclosporine C62H111N11O12 1203 5.0 5 12 15 279 85

lipstatin C29H49NO5 492 7.5 1 5 21 82 35

FK506 C44H69NO12 804 3.3 3 12 7 178 57

Average C46H70N4O14 917 2.2 7 15 16 259 64

Approved cancer drugs 1950-2010

Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311–335.

Natural product cancer drugs 1950-2010

DNA binders (13 drugs)

topoisomerase (11 drugs)

adenosine deaminase (1 drug)

microtubule (11 drugs)

farnesyltransferase (1 drug)

5-lipoxygenase (1 drug)

mTOR (1 drug)

histone deacetylase (1 drug)

unknown mechanism (2 drugs)

Natural product cancer drugs 1950-2010

0

200

400

600

800

1000

1200

1400

1600

1950 1960 1970 1980 1990 2000 2010 2020

Approval year

vs MW

Natural product cancer drugs 1950-2010 Approval Type MW XlogP3 HBD HBA rot PSA HA

sarkomycin 1954 NP 140 0.2 1 3 1 54 10

arglabin 1999 NP 246 1.7 0 3 0 39 18

streptozocin 1977 NP 265 -1.4 5 8 2 152 18

pentostatin 1992 NP 268 -2.1 4 5 2 112 19

ellipticinium 1983 ND 277 4.6 2 1 0 40 21

masoprocol 1992 NP 302 4.3 4 4 5 81 22

mitomycin C 1956 NP 334 -0.4 3 8 4 147 24

topotecan 1996 ND 422 0.5 2 7 3 103 31

belotecan 2004 ND 470 2 3 6 5 92 33

amrubicin 2002 ND 484 0.9 5 10 3 177 35

idarubicin 1990 ND 498 1.9 5 10 3 177 36

ixabepilone 2007 ND 507 3.6 3 6 2 140 35

daunomycin 1967 NP 528 1.8 5 11 4 186 38

romidepsin 2010 NP 541 2.2 4 8 2 193 36

doxorubicin 1966 NP 544 1.3 6 12 5 206 39

eprubicin 1984 ND 544 1.3 6 12 5 206 39

irinotecan 1994 ND 587 3 1 8 5 113 43

etoposide 1980 ND 589 0.6 3 13 5 161 42

carzinophilin 1954 NP 624 1.3 4 12 12 193 45 pirarubicin 1998 ND 628 2.7 5 13 7 204 45

teniposide 1967 ND 657 1.2 3 14 6 189 46

neocarzinostatin 1976 NP 662 2.3 4 13 8 175 48

valrubicin 1999 ND 724 4 5 16 11 215 51

eribulin 2010 NS 730 1.1 2 12 4 146 52

vindesine 1979 ND 754 2.7 5 10 7 165 55

trabectedin 2007 NP 762 3.4 4 15 4 194 54

vinorelbine 1989 ND 779 3.6 2 11 10 134 57

docetaxel 1995 ND 808 1.6 5 14 13 224 58

vinblastine 1965 NP 811 3.7 3 12 10 154 59

aclarubicin 1981 NP 812 3.8 4 16 10 217 58

vinflunine 2010 ND 817 4.4 2 13 10 134 59

vincristine 1963 NP 825 2.8 3 12 10 171 60

cabazitaxel 2010 ND 836 2.7 3 14 15 202 60

paclitaxel 1993 NP 854 2.5 4 14 14 221 62

solamargine 1989 NP 868 1.1 9 16 7 239 61

temsirolimus 2007 ND 1030 5.6 4 16 11 242 73

mithramycin 1961 NP 1085 0.6 11 24 15 358 76

chromomycin A3 1961 NP 1183 2.3 8 26 20 359 83

actinomycin D 1964 NP 1255 3.8 5 18 8 356 90

gemtuzumab ozogamicin 2000 ND 1368 2 8 27 24 410 84

peplomycin 1981 NP 1474 -6.7 21 26 38 696 102

bleomycin 1966 NP 1513 -1.9 21 29 36 770 101

AVERAGE 700.119 1.82381 4.928571 12.57143 8.714286 208.2619 49.47619

Nature’s rank

order:

log P >> HBD >

>rot > HBA >

MW = PSA >

HBA

Cutoff: MW 500, XlogP 5, HBD 5, HBA 10, rot 10, PSA 140, HA 30

Natural product lead to semi- or synthetic drug

Semisynthetic drug approvals 1981-2013

Total of 57 semisynthetic drugs

derived from 32 natural products.

Chemical modification improves:

•absorption / distribution

•metabolism / excretion

•toxicity

•target affinity / selectivity

•target resistance

Lucas Rezende, Flavio Emery

University of Sao Paulo-Ribeirao Preto

unpublished

From natural product to semisynthetic drug

From natural product to semisynthetic drug

80th percentile values

NP precursor Semisynthetic drug

MW 780 841

Xlog P 4.7 5.6

HBD 5.8 5.0

HBA 14 16

RotB 7 11

TPSA 203 218

Fsp3 0.8 0.8

(Ar – sp3) 0.8 -3

Chemical space for drug molecules

log P < 5, MW < 500

Small molecule drugs

Oral or non-oral

log P > 5, MW > 500

Molecular obesity

Liabilities likely

log P < 5, MW > 500

Middle space

Oral or non-oral

log P > 5, MW < 500

Lipophilic binding sites

Liabilities likely

Achieving bioavailability in middle space

•Natural products are high in sp3 hybridized carbon and escape

from flatland.

•Natural products are high in stereochemical features that

enforce rigidity and reduce conformational freedom e.g.

chirality, fused, bridging and spiro rings.

•Natural products often have internal H bonding to mask total

polar surface area.

•Natural products are often absorbed by active transport.

A Rule of Four for bioactive small molecules

•Log P ≤ 4 tracks aqueous / lipid distribution

•HBD ≤ 4 tracks aqueous solvation

•RotB ≤ 8 tracks promiscuity

•Fsp3 ≥ 0.4 tracks metabolism

A Rule of One

•Log P ≤ 4

Problematic chemical space- PAINS

Baell, J. B.; Holloway, G. A.

J. Med. Chem. 2010, 53, 2719-2740.

Baell, J. B.; Walters, M. A.

Nature 2014, 513, 481-483.

Problematic „cul de sac; compounds

Problematic chemical space- PAINS

Avoiding toxicophores in drug discovery

•Certain functional groups are considered to have a higher risk of toxicity.

R XR

O

O

O

R

O

R

•Aromatic amines, aromatic nitro compounds and thiocarbonyl derivatives. These

are examples of functional groups prone to be metabolized to other toxic species.

•These are guidelines, not absolute rules. There are drugs containing all the groups

on this slide, but they are rare.

NH2NO2

S

RR

•These are all alkylating agents. There is potential for non-specific alkylation of

nucleophilic groups in proteins or DNA, outside the desired target.

Examples of toxicophores in withdrawn drugs

Examples of toxicophores in successful drugs

paracetamol atorvastatin

Will release anilines upon amide hydrolysis

metronidazole betamethasone

Contain potentially reactive functional groups

23% of all FDA approved drugs in the period 1998-2007 originated from universities.

Kneller, R. Nature Rev. Drug Disc. 2010, 9, 867-882.

The origin of modern medicines