Druglikeness

Lipinski's rule

Lipinski’s Rule, so called “Rule of Five”, is published by Christopher A. Lipinski et al. in Pfizer Central Research (Groton, NJ,USA). They selected a subset of 2245 compounds from WDI (World Drug Index) database and defined drug-like character through this subset. The results are the followings: [ Lipinski,C.A. et al. Adv. Drug Deliv. Rev. 1997, 23, 3. ]

No. hydrogen bond donors ≤ 5 ( The sum of OHs and NHs )
No. hydrogen bond acceptor ≤ 10 ( The sum of Os and Ns )
Molecular weight ≤ 500
CLogP ≤ 5 ( MlogP ≤ 4.5 )

About 90 % of the above subset is included in defined rage with better solubility and permeability.

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Leadlike rule

Identification and optimization of lead compounds as chemical staring points are very important in combinatorial chemistry. Lead-like rule is published by Simon J. Teague et al. and defined to consider designing libraries with druglike physicochemical properties. They have divided the common sources of lead compounds for drug discovery into three types like the following figure. [ Teague,S.J.et al., Angew. Chem. Int. Ed. 1999, 38, 3743. ]

Figure. Group of Leads of Drug

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CMC-like rule

CMC-like rule is similar to rule of five. This is published by Arup K. Ghose et al.. They defined druglike character for the CMC database, which is removed several classes of compounds such as diagnostic imaging agents, solvents, and pharmaceutical aids. In this study, the qualifying range (covering more than 80% of the compounds) of the calculated log P is between -0.4 and 5.6, with an average value of 2.52. For molecular weight, the qualifying range is between 160 and 480, with an average value of 357. For molar refractivity, the qualifying range is between 40 and 130, with an average value of 97. For the total number of atoms, the qualifying range is between 20 and 70, with an average value of 48. The following table is about the qualifying range.

[ Ghose,A.K. et al. J. Comb. Chem. 1999, 1, 55. ]

drug class	Qualifying Range in CMC Database
drug class	AlogP (80%)	AMR (80%)	Molecular Weight (80%)	Number of Atoms (80%)
CMC clean	-0.4 ~ 5.6	40 ~ 130	160 ~ 480	20 ~ 70
inflammatory	1.4 ~4.5	59 ~ 119	212 ~ 447	24 ~ 59
depressant	1.4 ~ 4.9	62 ~ 114	210 ~ 380	32 ~ 56
psychotic	2.3 ~ 5.2	85 ~ 131	274 ~ 464	40 ~ 63
hypertensive	-0.5 ~ 4.5	54 ~ 128	206 ~ 506	28 ~ 66
hypnotic	0.5 ~ 3.9	43 ~ 97	162 ~ 360	20 ~ 45
neoplastic	-1.5 ~ 4.7	43 ~ 128	180 ~ 475	21 ~ 63
infective	-0.3 ~ 5.1	44 ~ 144	145 ~ 455	12 ~ 64

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MDDR-like rules

MDDR-like rule is published by Tudor I. Oprea. The rule of five test produced similar results when applied to the ACDF and MDDRF subset, which 80% of ACDF and MDDRF pass the rule of five test. ACD database is non-drug database and MDDR database is drug database. ACDF and MDDRF are databases removed the reactive functional groups such as acyl-halides, sulfonyl-halides, Michael acceptors, etc.. In this study, therefore, he has concluded that the rule of five test cannot be used to discriminate between drugs and non-drugs. Descriptors used to MDDR-like rule are the number of rings, the number of rigid bonds and the number of rotatable bonds.

The probability of finding a ‘druglike’ compound is higher in its ranges (e.g., No.Rings ≥ 3, No. Rigid bonds ≥ 18, No. Rotatable bonds ≥ 6), while the probability of finding a ‘nondrug-like’ compound is higher in the ranges (e.g., No.Rings ≤ 2, No. Rigid bonds ≤ 17, No. Rotatable bonds ≤ 5). There is more information in the table below. In PreADMET, The result from MDDR-like rule is represented as classification of the following table and this rule can be customized by user. (Figure 5.5)

[ Oprea,T.I. J. Comput. Aid. Mol. Des. 2000, 14, 251. ]

	Condition
drug-like	No. Rings ≥ 3 No. Rigid bonds ≥ 18 No. Rotatable bonds ≥ 6
nondrug-like	No. Rings ≤ 2 No. Rigid bonds ≤ 17 No. Rotatable bonds ≤ 5
mid-structure	structures of the other ranges

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Reactive functional group

Filtering by reactive functional group is the one of the important steps for the drug discovery. A compound with a reactive functional group is reactive in human body, and it has possibility to cause toxicity. Additionally, a compound with a reactive functional group leads to reaction during a process of an in vitro experiment, such as a case of HTS. This may results some serious error of activity for drug.

These compounds can be filtered off or removed, at the beginning of drug discovery. This filtering reduces probability of causing toxicity or error. PreADMET can find compounds with electrophilic functional group which tends to make a covalent bond with protein, causing false positive. And PreADMET also finds compounds with 3 prohibited functional groups that are extremely unusual in drug discovery. The number of both kinds of functional groups are 23 in total.

[ (1) Rishton,G.M. DDT. 1997, 2, 382. (2) Walters,W.P. et al. Adv. Drug Deliv. Rev. 2002, 54, 255. ]

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WDI-like rule

This measurement is based on compounds that have molecular properties within the 90 % upper bound found in the WDI (World Drug Index).

[ Brown,R.D. et al. ”Tools for designing diverse, drug-like, cost-effective combinatorial libraries”; in Combinatorial Library Design and Evaluation”, Marcel Dekker, Inc. New York, 2001, 328. ]

Descriptors	90% cutoff	Descriptors	90% cutoff
MW	550	Kappa-2A	12
Rotbond	13	Kappa-3A	8
Hbond acceptor	9	CHI-V-0	20
Hbond donor	5	CHI-V-1	12
AlogP	5	CHI-V-2	10
MolRef	120	CHI-V-3P	8
Balaban Jx	2.8	CHI-V-3C	2.2
PHI	8	Wiener	4000
Kappa-1A	25	Zabreb	175

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