The document discusses Reaxys Medicinal Chemistry and how it supports hit-to-lead and lead optimization processes. It provides high quality data on topics like efficacy, ADMET properties, and animal models to help computational and medicinal chemists. The pX concept normalizes bioactivity measurements like IC50, Ki, and % inhibition into a single comparable metric, making it possible to compare compound affinity regardless of the metric reported. This allows researchers to more easily search for and analyze active compounds.

1. Olivier Barberan
Senior Product Manager
New Reaxys Medicinal Chemistry: your lead
optimization solution

2. Key challenges in drug discovery and Lead
optimization
How NEW Reaxys Medicinal Chemistry supports Hit
to lead and Lead Optimization based with live
examples
Q&A
Summary

3. Productivity in pharmaceutical
development is at an all-time low
considering rising costs of R&D
Drop In FDA Approvals Rekindles
Fears For The Future Of Pharma:
2016 is a challenge!
Pharma companies are challenged to improve their R&D
outcomes

4. Target ID &
Validation
Lead ID &
Validation
Pre-
clinical
Clinical
(Phase I to III)
Post-
Launch
Characterize &
understand
disease
Identify, design &
validate leads
Cull/prioritize
leads
Determine safety
and efficacy profile
Manage risk &
compliance; improve
patient care
Source: Tufts Center for the study of drug development, Nov 2014
$125 M $773 M $200 M $1,460 M $3–5 B
Cost (/NME)
“We cannot fail for reasons we could have predicted.
We should fail only for reasons we could not predict.”
—Dr Moncef Slaoui
Head of Global R&D, GSK
• Low margin of safety is a major
cause of attrition in Phase I and II
• Lack of efficacy is a major cause
of attrition in Phase II and III
Better informed decisions at the Lead
ID & Validation stage generates
more optimized leads and mitigates
failures and miss-investments
80% 65% 69% 12%
Success Rate
Investing in earlier development stages builds up the
pipeline and reduces attrition from foreseeable causes

5. Deliver smarter lead compounds
Optimize efficacy and potency on
animal model disease
Deliver safer lead compounds
Higher chance of success rate in the
development process
High-
throughput
screening
Synthesis
of analogs
Improve
efficacy cell
assays
Improve
selectivity
Improve
affinity on
“on target”
Optimize
metabolism
Optimize
Pharmacokinetic
Optimize
Cell
penetration
New analogs
improved
potency
Reduced
off-target
activities
Optimize
efficacy on
Animal M.
Decrease In
vitro Toxicity
Hit/lead
Optimization
What are chemists in hit to lead identification trying to
achieve?

6. Potency &
selectivity
DMPK properties
Physical properties
Safety
pharmacology
The lead optimization challenge: Optimization of early
substance to potential drug

7. Substances
Chemical structure ,Name, code, synonym of compound, calculated
physchem properties (log P, HBA, HBD, PSA, RotB), Lipinski rules of 5
Druggable target
Explore Target affinity patterns of chemical
compounds
In vitro and Cell Based assays
In vitro assays (binding, second messenger etc..) and Cell based assays for
example : Aggregation, Angiogenesis, Apoptosis, Cell differentiation, etc…
Animal models disease
Zucker rats for obesity model, ovariectomized rat in osteoporosis, treatment
of glaucoma, Xenografted animals with tumors to test antineplastic drugs
Pharmacokinetic and ADME Properties
Metabolic stability, Intrinsic clearance, Half life of elimination, Bioavailability,
In vivo Clearance
Toxicity
Cytotoxicity, cardiotoxicity, chronic
toxicity
Reaxys Medicinal Chemistry coverage

8. “The power of Reaxys Medicinal Chemistry is that the data are ready
to be discovered, used, digested and analyzed.
That laborious work of preparing the data is done. The user can now
focus on gaining insights.”
• millions of data points in
Reaxys Medicinal Chemistry
can serve as direct input for
any desired analysis.
• The pX value featured in the
database is a standardized
measure of affinity.
• The heatmap in the Reaxys
Medicinal Chemistry user
interface capitalizes on this
comparability to provide an
interactive matrix that
summarizes affinity for a
large number of compound–
target pairings and can be
used to explore factors that
contribute to affinity or find
interesting activity hotspots

9. Parameter Filter
Normalization of bioactivites pX Concept?
Parameter Grinder
IC50, Ki, % Inhibition, %,EC50, pKi, ED50, pIC50, AUC, Emax(%),
Concentration, Cmax, nH, pA2, % Stimulation, Tmax, Fold
increase, t1/2 el, Rate, Number, Kd, pEC50, pKb, IA (%), Time, Km,
ID50, Delta, Vmax, Cl, Clint, Ue(%), pD2, %max, Kb, Bmax, Cavg,
Pressure, Amount, t1/2, Cl/F, Cmin, MED, fu, F(%), Dose, ClR,
AUC i/AUC, LD50, Frequency
PARAMETERS RELATED TO CONCENTRATION
pIC50, pEC50, pED50, pID50, pLC50, pLD50, pKi, pKd, pKb, pGI, pD2,
pD’2, pA2 , IC50, IC20, IC80, EC50, ED50, ID50, LC50, LD50, CC50, CD50,
CIC50, CID50, GI, MBC, MCC, MEC, MED, MFC, MIC, TGI, Ki, Kd,
Kb, Ka, Ke , Km,Kapp,Kic, Kiu, % Inhibition
pIC50, pEC50, pED50, pID50, pLC50, pLD50, pKi, pKd, pKb, pGI, pD2,
pD’2, pA2 , IC50, IC20, IC80, EC50, ED50, ID50, LC50, LD50, CC50, CD50,
CIC50, CID50, GI, MBC, MCC, MEC, MED, MFC, MIC, TGI, Ki, Kd,
Kb, Ka, Ke , Km,Kapp,Kic, Kiu, % Inhibition
pX is computed
Filter value for concentration
based parameters
Normalization to a single
comparable metric
Original values are preserved; this is an additional
computed descriptor

10. Computation of pX value: - log (Affinity) and affinity
results
Like pIC50, pEC50, pED50, pID50, pLC50, pLD50, pKi, pKd, pKb, pD2, pD’2, pA2
 pX = pIC50 etc….
Remark
If values are expressed in Weight/voluem( like g/l), they are first converted in M (using molecular
weight, animal/tissue weight or volume)
Results are expressed as –log10 (affinity)
IC50, EC50, ED50, ID50, LC50, LD50, Ki, Kd, Kb, Ka, Ke
pX= -log10(IC50)
Results are expressed as affinity

11. Hit to lead : Virtual screening

12. Ligand Based virtual Screening – Using Reaxys
Medicinal Chemistry
Objective
• Describe an In Silico Screening approach
using Reaxys Medicinal Chemistry
Case Study on T-Type calcium channels

13. Ligand-Based In Silico Screening
Filter on active
compound pX>7
ANSWERS
730 compounds
Simple Target name
search returns all
results

14. Ligand-Based In Silico Screening
730 Query structures
Representation & Chemical
Space Molecular descriptors &
Fingerprints
Virtual Screening
Pharmacophoric Similarity
N
O
N
N
N
O
N
N
N
314 Hits
"Drug-like" Filtering
1. Molecular diversity and chemical originality
2. Compounds availability
39 compounds ordered for testing
28 M Substances
Chemical space based on
Synthesized substances

15. Biological activity
Electrophysiology experiments: Screening @10
µM on Cav3.2 T-Type channels
9 compounds with a % inhibition > 75%
15 compounds with a % inhibition >50%

16. Lead Optimization

17. Potency &
Selectivity
DMPK Properties
Physical properties
Safety
pharmacology
Lead optimization

18. ADMET Properties influencing medicinal
Chemistry design
• logD7.4
• Protein Binding
• Solubility
• Metabolic
Stability
• hERG
• Etc…
Step1
•Rat PPB
• Hu heps
• CYP inhib
• Caco2
• NaV1.5
• Etc…
Step2
• logD7.4
• Solubility
•Protein Binding
• hERG
• Rat PPB
• Metabolic
Stability
• CYP inhib
• Caco2
• etc.
Step 0

19. Wrap Up
“They care mostly about
Accessing our data through
API Knime Pipeline pilot”
“They want a product they can
use right out of the box”
New Reaxys Medicinal Chemistry is supporting Hit to lead and lead
optimization process by providing relevant and high quality data to scientists
by improving
Computational Chemists
High quality data on many
different topics (efficacy , ADMET,
Animal models)
Large Amount of data to Perform
models
Medicinal Chemists
Accessing the data through third
party tools
Reaxys Medicinal Chemistry is able to support both Computational and
Medicinal chemist

20. Q&A

21. 2
1
pX concept competitive advantage
• Augment (not replace) original data
• Make it possible to compare affinity of compounds using different reported metrics
Examples: IC50, Ki % inhibition
• Make it possible to search for active compounds regardless of metric reported
• Insure end users to encompass all the affinity data that they are searching for without
being an expert (knowing all the parameters and units used in publications)
• Facilitate analysis using third party tools (Spotfire, Pipeline Pilot) through the export.
pX it’s a unique way of quantifying affinity of compounds on targets

22. Parameter Filter
22
pX concept ?
Parameter Grinder
IC50, Ki, % Inhibition, %,EC50, pKi, ED50, pIC50, AUC, Emax(%),
Concentration, Cmax, nH, pA2, % Stimulation, Tmax, Fold
increase, t1/2 el, Rate, Number, Kd, pEC50, pKb, IA (%), Time, Km,
ID50, Delta, Vmax, Cl, Clint, Ue(%), pD2, %max, Kb, Bmax, Cavg,
Pressure, Amount, t1/2, Cl/F, Cmin, MED, fu, F(%), Dose, ClR,
AUC i/AUC, LD50, Frequency
PARAMETERS RELATED TO CONCENTRATION
pIC50, pEC50, pED50, pID50, pLC50, pLD50, pKi, pKd, pKb, pGI, pD2,
pD’2, pA2 , IC50, IC20, IC80, EC50, ED50, ID50, LC50, LD50, CC50, CD50,
CIC50, CID50, GI, MBC, MCC, MEC, MED, MFC, MIC, TGI, Ki, Kd,
Kb, Ka, Ke , Km,Kapp,Kic, Kiu, % Inhibition
pIC50, pEC50, pED50, pID50, pLC50, pLD50, pKi, pKd, pKb, pGI, pD2,
pD’2, pA2 , IC50, IC20, IC80, EC50, ED50, ID50, LC50, LD50, CC50, CD50,
CIC50, CID50, GI, MBC, MCC, MEC, MED, MFC, MIC, TGI, Ki, Kd,
Kb, Ka, Ke , Km,Kapp,Kic, Kiu, % Inhibition
pX is computed
Filter value for concentration
based parameters
Normalization to a single
comparable metric
Original values are preserved; this is an additional
computed descriptor

23. 23
Computation of pX value: - log (Affinity) and affinity results
Like pIC50, pEC50, pED50, pID50, pLC50, pLD50, pKi, pKd, pKb, pD2, pD’2, pA2
 pX = pIC50 etc….
Remark
If values are expressed in Weight/voluem( like g/l), they are first converted in M (using molecular
weight, animal/tissue weight or volume)
Results are expressed as –log10 (affinity)
IC50, EC50, ED50, ID50, LC50, LD50, Ki, Kd, Kb, Ka, Ke
pX= -log10(IC50)
Results are expressed as affinity

24. How the pX is Calculated ? : ICF (25 ≤ F<95)
Like pICF, pECF, pEDF, pIDF, pLCF, pLDF are transformed into pIC50, pEC50, pED50,
pID50, pLC50, pLD50 using
Results are expressed as –log(affinity)
ICF, ECF, EDF, IDF, LCF, LDF where 25≤ F <95 are transformed into IC50, EC50, ED50,
ID50, LC50, LD50
Results are expressed as affinity
pX= 𝐩𝐈𝐂 𝟓𝟎 = 𝐩𝐈𝐂 𝐅 − 𝐥𝐨𝐠
𝟏𝟎𝟎−𝐅
𝐅
where 25≤ F <95
IC50= 𝑰𝑪 𝑭
𝟏𝟎𝟎−𝑭
𝑭
where 25≤ F <95 and pX=-log(IC50)

25. How the pX is calculated? : -log (Affinity) results with Modulators
Like pIC50, pEC50, pED50, pID50, pLC50, pLD50, pKi, pKd, pKb, pD2, pD’2, pA2
If pIC50 etc….≤ 5 pX = 1
If pIC50 etc….> 5 pX= pIC50 etc … (Without modulator for pX)
Results are expressed as –log10 (affinity) with modulator s <,#<,<=,<<
Results are expressed as –log10 (affinity) with modulator s >,#>,>=,>>
Like pIC50, pEC50, pED50, pID50, pLC50, pLD50, pKi, pKd, pKb, pD2, pD’2, pA2
pX= pIC50 etc … (Without modulator for pX)

26. How the pX is calculated? : Affinity results with Modulators
IC50, EC50, ED50, ID50, LC50, LD50, Ki, Kd, Kb, Ka, Ke
If IC50 etc….> 10 µM pX = 1
If IC50 etc….≤ 10µM pX= -log(IC50) etc … (Without modulator for pX)
Results are expressed as affinity with Modulators >,#>,>=,>>
IC50, EC50, ED50, ID50, LC50, LD50, Ki, Kd, Kb, Ka, Ke
pX= -log(IC50) etc … (Without modulator for pX)
Results are expressed as affinity with Modulators <,#<,<=,<<

27. How the pX is calculated? : affinity and –log(affinity) results and Ranges
Like pIC50, pEC50, pED50, pID50, pLC50, pLD50, pKi, pKd, pKb, pD2, pD’2, pA2
If pRangemax –pRangemin < 3 pX = pRangemax
If pRangemax –pRangemin ≥ 3 pX is not calculated
Results are expressed as –log(affinity) with Ranges
IC50, EC50, ED50, ID50, LC50, LD50, Ki, Kd, Kb, Ka, Ke
If
Rangemax
Rangemin
< 1000 pX = -log(Rangemin)
If
Rangemax
Rangemin
≥ 1000 pX is not calculated
Results are expressed as affinity with ranges

28. How the pX is Calculated ? : % inhibition
Results are expressed % of inhibition
% of inhibition are converted into IC50 when
a concentration of the tested compound is
available using the following equation and
assumptions
- Hill slope = 1 (nh)
- % of inhbition between 25% and 95%
- Concentration of the compound is not Available
pX is not calculated
- Concentration of the compound is available as :
 Range pX is not calculated
 Single value pX is calculated as follow
o If %inhibition <25 pX = 1
o If 25 ≤ % inhibition <95 pX =-Log (IC50) using eq.1
o If % inhibition ≥ 95 % inhibition =95 and pX =-Log (IC50) using eq.1
% inhibition is available as Single value
- Concentration of the compound is not Available
pX is not calculated
- Concentration of the compound is available as :
 Range pX is not calculated
 Single value pX is calculated as follow
%inhibitionaverage=(%inhibitionmax+%inhibitionmin)/2
o If %inhibition Average <25 pX = 1
o If 25 ≤ % inhibitionAverage <95 pX =-Log (IC50) using eq.1
o If % inhibitionAverage ≥ 95 % inhibition Average =95 and pX =-Log
(IC50) using eq.1
% inhibition is available as Range
Eq.1

29. How the pX is Calculated ? : Qualitative results
- Not Active (NA)
pX = 1
- @ Active
Concentration of the compound is not Available
pX is not calculated
Concentration of the compound is available
Range pX = -Log [Concentration min]
Single value pX = -Log [Concentration]
Results are expressed as Qualitative