Druggability of NCEs

Druggability of NCEs

1. DRUGGABILITY OF NEW CHEMICAL ENTITIES Presented by Dheeraj Kumar M.S. (Pharm.) 1 st Semester Id No : 443/17 Pharmaceutics National Institute of Pharmaceutical Education And Research, Raebareli 3-Dec-17 1

2. Contents New Chemical Entities Sources of NCEs Drug Discovery Process Druggability Rules for Determination of Druggability Conclusions References 3-Dec-17 2

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. 3-Dec-17 3

4. SOURCES OF Nces Plant sources Synthetic chemistry Animal sources Combinatorial chemistry Microbial sources Marine sources Natural sources Synthetic Approch 3-Dec-17 4

5. Drug Discovery Process Fig.1: Traditional Drug Discovery Fig.2: Modern D rug D iscovery 3-Dec-17 5

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. 3-Dec-17 6

7. Typical acceptable Pharmaceutical properties Aqueous solubility Permiability Satisfactory stability to metabolizing enzymes Resistant to gastric pH 3-Dec-17 7

8. Rules For Determination Of Druggability 1)Lipinski's rule- Fig.3: Lipinski’s rule (Source: Koster et al, 2011) . 3-Dec-17 8

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. 3-Dec-17 9

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. 3-Dec-17 10

11. Cont…. 3-Dec-17 11 Table 1: Marketed products not following Lipinski ’ s rule

12. Other Druggability Rules 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) 3-Dec-17 12

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 sp 3 hybridized carbon atom and presence of chiral carbon center correlate with success as compounds transition from discovery. (Lovering et al. , 2009) 3-Dec-17 13

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.   3-Dec-17 14

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 . 3-Dec-17 15

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. 3-Dec-17 16

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. 3-Dec-17 17

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