This document discusses the druggability of new chemical entities (NCEs). It defines druggability as the ability of a compound to be used commercially as a pharmaceutical drug after undergoing clinical trials. Several rules for determining druggability are described, with Lipinski's rule of five being the most popular. Lipinski's rule states that good oral bioavailability is more likely if a compound has less than 5 H-bond donors, 10 H-bond acceptors, a molecular weight below 500 Daltons, and a logP value below 5. The document also discusses other druggability rules and exceptions to Lipinski's rule.

1. DRUGGABILITY OF NEW
CHEMICAL ENTITIES
Presented by
Dheeraj Kumar
M.S. (Pharm.) 1stSemester
Id No : 443/17
Pharmaceutics
National Institute of Pharmaceutical Education And Research, Raebareli
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2. Contents
• New Chemical Entities
• Sources of NCEs
• Drug Discovery Process
• Druggability
• Rules for Determination of Druggability
• Conclusions
• References
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3. New Chemical Entities
NCE is a molecule developed by R&D scientist in
the early stage of drug discovery.
NCE after clinical trails could be converted into
drug.
NCEs can be developed from natural sources or
synthesized in laboratory.
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4. SOURCES OF Nces
Plant sources Synthetic chemistry
Animal sources Combinatorial chemistry
Microbial sources
Marine sources
Natural
sources
Synthetic
Approch
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5. Drug Discovery Process
Fig.1: Traditional Drug Discovery Fig.2: Modern Drug Discovery
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6. Druggability
• Also called Drug likeness.
• The ability of a compound, molecule, or new
chemical entity to be used commercially as a
pharmaceutical drug.
• After clinical trails could be used as drug.
• Compounds should have acceptable pharmaceutical
properties along with biological activity.
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7. Typical acceptable Pharmaceutical properties
• Aqueous solubility
• Permiability
• Satisfactory stability to metabolizing enzymes
• Resistant to gastric pH
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8. Rules For Determination Of Druggability
1)Lipinski's rule-
Fig.3: Lipinski’s rule
(Source: Koster et al, 2011)
.
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9. • Out of these four, if more than one property fails then
the compound is unlikely to be further pursued as
potential drug
• 90% of the drugs follow Lipinski's rule.
• Most anti-TB drugs and antibacterial drugs don’t
follow this rule.
• Compounds which are substrates for biological
transporters and peptidomimetics are exceptions of
this rule.
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10. Exceptions of Lipinski’s rule
90% of the orally active drugs available in the market
follow Lipinski’s rule of five. Some of the exceptions
of Lipinski’s rule of 5 are:-
• Compounds that are substrate for biological
transporters.
• Peptidomimetics.
• Most anti-TB and antibactrials don’t follow
Lipinski’s rule of 5.
• Some natural products also don’t follow Lipinski’s
rule of 5.
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11. Cont….
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Table 1: Marketed products not following
Lipinski’s rule

12. Other Druggability Rules
1) Veber’s rule
Majority of compounds with good oral
bioavailability in had less than 10 rotatable bonds
(ROTB) and polar surface area (PSA) less than 140
Å. (Veber, et al. , 2002)
2) Hughe’s rule
Compounds with log P less than 3 and PSA greater
than 75 Å were six times less likely to exhibit adverse
events in in‐vivo tolerance studies. (Hughes, et al,
2008)
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13. Cont…
3) Ritchie’s rule
Number of aromatic rings greater than 3 significantly
increases the risk of compound attrition.
4) Lovering’s rule
Lovering’s rule states that the sp3 hybridized carbon
atom and presence of chiral carbon centercorrelate
with success as compounds transition from discovery.
(Lovering et al. , 2009)
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14. Conclusions
From the above study we concluded that there are
certain rules to predict the druggability, out of which
Lipinski’s rule of five is the most popular and most
accurate. Before 2003, 50% of newly discovered
molecule in market failed because of druggability
problem, because at that time there was no rule to
predict Druggability. But after, 2003 the failure rate
of NCEs due to druggability reduces to 10% from
50% after the Lipinski’s rule was given in 1997 by
Christopher A. Lipinski. If a newly discovered
molecule complies with Lipinski’s rule of five then
there is 90% possibility that the molecule will be
orally bioavilable.
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15. REFERENCES
• Shayne G.C. Drug discovery Handbook, John Wiley
& sons publications, 3rd edition, 81-84, 2005.
• Lipinski A.C. Lead and drug like compounds: the
rule-of-five revolution, Drug Discovery Today, 1,
337-341, 2004.
• Hopkins A.L. . and Groom C.R., The druggable
genome, Nat. Rev. Drug Discovery, 727-730, 2002.
• Lipinski. A.C. Dominy W.B. Lombardo F. and Feeney
P.J., Experimental and computational approaches to
estimate solubility and permeability in drug discovery
and development settings, Advanced Drug Delivery
Reviews, 64, 4-17, 2012
• Vistoli G. Pedreti A. and Testa B. Assessing drug
likeness-what are we missing, Drug Discovery today,
13, 7-8, 2008.
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16. Cont…
• Sirois S. Hatzakis G. Du Q. and Chou K.C.
Assessment of chemical libraries for their
Druggability, Computational Biology Chemistry 29,
55–67, 2005.
• Xavier Barril, Druggability predictions: methods,
limitations, and applications, WIREs Computational
Molecular Science 3-12, 2012.
• Perola E., Development of a Rule-Based Method for
the Assessment of Protein Druggability, Journal of
Chemical Information and Modelling, 1027-1038,
2012.
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17. Cont…
• Veber D.F. Johnson S.R. Cheng H.Y. Smith B.R.
Ward K.W. and Kopple K.D. Molecular Properties
That Influence the Oral Bioavailability of Drug
Candidates, Jouranl of Medicinal chemistry, 2615-
2623, 2002.
• Hughes J.P. Res S. Kalindjin S.B. and Philphot K.L.
Principles of early drug discovery, British Journal of
Pharmacology, 162, 1239-1249, 2011.
• Keller H.T. Pichota A. and Yin Z,A Practical view of
Druggability, Current Opinion in Chemical Biology,
10, 357-361, 2006.
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