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Table 10.7 is self-explanatory for assessing the different parameters for the toxicity of
any new drug molecule. It gives us a better idea about where our proposed drug mol-
ecule can be toxic and how exposure to that area can be avoided.
Tab. 10.7 (continued)
S. no. Name of
drug
hERG
blocker
Human
hepatotoxicity
Skin
sensitization
Carcinogenicity Respiratory
toxicity
Rosuvastatin –
(May not
interfere)
++
(Probably
hepatotoxic)
–
(Not a skin
irritant)
++
(Probably
carcinogenic)
++
(Probably
respiratory
toxic)
Cetirizine –
(May not
interfere)
++
(Probably
hepatotoxic)
–
(Not a skin
irritant)
–
(Not a probable
carcinogenic)
++
(probably
respiratory
toxic)
Pantoprazole –
(May not
interfere)
+++
(Probably
hepatotoxic)
–
(Not a skin
irritant)
+++
(Probably
carcinogenic)
+++
(Probably
respiratory
toxic)
Glimepiride –
(May not
interfere)
+
(Little
probability of
hepatotoxic)
–
(Not a skin
irritant)
–
(Not a probable
carcinogenic)
–
(Nontoxic)
Donepezil +++
(Probably
hERG
blocker)
–
(Very little
probability of
being toxic)
–
(Not a skin
irritant)
–
(Not a probable
carcinogenic)
+++
(probably
respiratory
toxic)
Quinine –
(Very little
probability
of being a
blocker)
+++
(Probably
hepatotoxic)
–
(Not a skin
irritant)
++
(Probably
carcinogenic)
+++
(Probably
respiratory
toxic)
Lidocaine –
(May not
interfere)
–
(Nontoxic)
+
(Little irritant to
the skin)
–
(Not a probable
carcinogenic)
+++
(Probably
respiratory
toxic)
10.7 Toxicity aspects of the drug molecule 239
10.8 Drug-likeness profile of the newly proposed drug molecule
Besides the ADMET profile of any drug molecule, there is another popular concept of
“drug-likeness” among the research fraternity for designing any new drug molecule.
Drug-likeness is defined as how close our drug molecule is with r espect to certain
properties when compared with the already existing drug molecules. The drug-
likeness profile assesses whether a compound possesses the characteristics and prop-
erties that are typical ly associated with successful drugs. A favorable drug-likeness
profile increases the likelihood of a compound progressing through the drug develop-
ment pipeline. Several key factors contribute to a drug’s likeness profile in CADD and
are given below.
– Physicochemical properties: CADD analyzes prope rties like molecular weight,
lipophilicity, hydrogen bonding capacity, and polar surface area. A drug molecule
should typically fall within specific ranges for these prope rties to be considered
drug-like.
– Structural features: The compound’s chemical structure is evaluated for specific
motifs or functional groups associated with drug-likeness. Toxicophores or struc-
tural alerts that indicate potential toxicity are also screened.
– Pharmacokinetics and ADME: Computational tools assess how the molecule is
likely to behave in terms of absorption, distribution, metabolism, and excretion
(ADME). Favorable ADME properties are essential for a drug to be effective
and safe.
– Biological activity: CADD predicts a compound’s affinity for its target protein,
ensuring that it is likely to bind effectively and exert the desired pharmacological
effects.
– Safety profile: Potential toxicities and side effects are predicted, including risks
to major organs like the liver and heart.
– Comparative analysis: The drug-likeness profile is often compared to existing
drugs in the same therapeutic class or category to gauge its similarity and poten-
tial competitive advantage.
By rigorously assessing these factors, CADD helps researchers make informed deci-
sions about whether a newly proposed drug molecule is worth pursuing, streamlining
the drug discovery process, and reducing the costs and risks associated with bringing
new medications to market. Different researchers have given different rules for the
drug-likeness behavior of any newly proposed drug candidate and the most popularly
employed among them in drug designing are:
240 Chapter 10 ADMET analysis in CADD
10.8.1 Lipinski’s rule of five
Lipinski’s rule of five, a cornerstone of computer-aided drug design (CADD), offers a
set of guidelines to assess the drug-likeness of a newly proposed molecule. These
rules, established by Dr. Christopher Lipinski in 1997, are used to predict a com-
pound’s oral bioavailability and its potential as a viable drug candidate [57].
The rule stipulates that a drug molecule should meet the following criteria:
– Molecular weight (MW) ≤ 500 Da: Compounds exceeding this limit may have dif-
ficulty crossing biological membranes.
– LogP (Octanol–water partition coefficient) ≤ 5: This parameter measures a
molecule’s lipophilicity; excessively lipophilic compounds may face absorpt ion
issues.
– Hydrogen bond donors ≤ 5: Compounds with too many hydrogen bond donors
may struggle to permeate cell membranes.
– Hydrogen bond acceptors ≤ 10: A high number of hydrogen bond acceptors can
hinder oral bioavailability.
Adhering to Lipinski ’s rule of five is not a strict requirement but serves as a practical
guideline. Compounds that meet these criteria often have better chances of becoming
successful drugs because they tend to exhibit improved pharmacokinetic properties
and oral absorption. CADD tools and software can rapidly analyze a newly proposed
molecule against these rules, aiding in the early-stage selection of drug candidates
with favorable drug-like properties, thus saving time and resources in the drug devel-
opment process.
The above conditions were proposed by Lipinski for orally active drugs and two
more conditions to this are added by the Veber and are given below.
– No. of rotatable bonds in the molecule should not be greater than 10.
– The total polar surface area (TPSA) of the compound should be less than 140.
Table 10.8 depicts the values of the above conditions for some of the commonly mar-
keted drugs, calculated from the SwissADME server [24].
10.8.2 Muegge (Bayer) filter of drug-likeness
Muegge (Bayer) filter of drug-likeness, developed by Dr. Irmgard Muegge at Bayer
Pharmaceuticals in 2001, is an essential tool in CADD for assessing the drug-likeness
of newly proposed drug molecules [58, 59]. It serves as a valuable filter to screen and
prioritize compounds with a higher likelihood of success in the drug discovery pro-
cess. This filter is designed to evaluate the chemical and physicochemical properties
of a molecule to determine if it meets the criteria of a “drug-like” compound. The key
features considered by the Muegge filter include molecular weight, lipophilicity, polar
10.8 Drug-likeness profile of the newly proposed drug molecule 241
surface area, and the number of hydrogen bond donors and acceptors. These parame-
ters are critical because they influence a compound’s ADME properties and its overall
pharmacokinetic profile. The Muegge filter helps medicinal chemists and drug design-
ers to quickly eliminate molecules that are likely to exhibit poor bioavailability or
have a high risk of toxicity, thus saving time and resources in the drug development
process. Compounds that pass this filter are more likely to progress to further stages
of development. In essence, theMuegge(Bayer)filterisavaluablecomponentof
CADD that aids in the rational selection and optimization of drug candidates by focus-
ing on drug-likeness criteria, ultimately increasing the chances of identifying success-
ful therapeutic agents with improved chances of reaching the market.
According to Muegge, a compound must meet the following conditions to be con-
sidered as a drug-like molecule:
– 200 ≤ molecular weight ≤ 600
– −2 ≤ X log p ≤ 6
– Total polar surface area (TPSA) ≤ 150
– The total number of rings in the molecule should be ≤7
– The number of hydrogen bond donors should not be greater than 5
– The number of hydrogen bond acceptors should not be greater than 10
– Total number of carbon should be greater than 4
– The number of heteroatoms should be greater than 1
– The number of rotatable bonds in the molecule should not be greater than 15
Table 10.9 depicts the values of these parameters for some of the marketed drugs as
per Muegge’s filter, calculated from the SwissADME online server.
Tab. 10.8: Values of the above conditions for some of the commonly marketed drugs calculated from the
SwissADME server.
S. no. Name of
drug
Molecular
weight
No. of
H-bond
donors
No. of
H-bond
acceptors
Log P
value
No. of
rotatable
bonds
TPSA No. of
violations
Paracetamol . .
Clonazepam . . .
Captopril . .
Rosuvastatin . . .
Cetirizine . . .
Pantoprazole . . .
Glimepride . . .
Donepezil . . .
Quinine . . .
Lidocaine . . .
242 Chapter 10 ADMET analysis in CADD
Tab. 10.9: Values of various parameters for some of the marketed drugs as per Muegge’s filter, calculated from the SwissADME online server.
S. No. Name of
drug
Molecular
weight
No. of
H-bond
donors
No. of
H-bond
acceptors
Log P
value
No. of
rotatable
bonds
TPSA No. of
rings
No. of
heteroatoms
No. of carbon
atoms
No. of
violations
Paracetamol . .
Clonazepam . . .
Captopril . .
Rosuvastatin . . .
Cetirizine . . .
Pantoprazole . . .
Glimepride . . .
Donepezil . . .
Quinine . . .
Lidocaine . . .
10.8 Drug-likeness profile of the newly proposed drug molecule 243
Along with the above mentioned most common drug-likeness rules, there are cer-
tain additional rules that have been defined by researcher s for drug-likeness of any
new proposed drug candidate. These rules are summarized in Tab. 10.10.
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244 Chapter 10 ADMET analysis in CADD
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Chapter 11
De novo drug designing approaches
De novo drug design in CADD relies on algorithms and computational models to predict the inter-
actions between small molecules and biological targets, paving the way for the discovery of novel
therapeutics with tailored properties. – Dr. Jane Smith
11.1 Introduction
De novo drug design re prese nts a transformative approach in the development of
novel pharmaceutical compounds [1]. Unlike traditional drug discovery methods,
which rely on identifying existing molecules with therapeutic potential, de novo drug
design starts from scratch, constructing entirely new molecules tailored to target spe-
cific diseases [2, 3]. This innovative approach leverages computational techniques and
molecular modeling to design molecules with desired biological activities. De novo
drug design is characterized by its computational prowess, drawing from the fields of
bioinformatics, molecular modeling, and artificial intelligence to expedite the identifi-
cation of promising drug candidates [4–6].
Central to de novo drug design is the concept of rational drug design, which re-
lies on a deep understanding of the target biomolecule’s structure and function [7].
Scientists employ various computational tools and algorithms to predict the three-
dimensional structure of the target protein, usually a key player in a disease path-
way [8–10]. This predictive modeling allows researchers to identify p otential bind-
ing sites and interaction points on the t arget, providing invaluable insights for drug
design. Once the target’s structure is elucidated, de novo drug design algorithms
come into play [11]. These algorithms utilize vast databases of chemical compounds
to generate new molecular structures with the potential to interact effectively with
the t arget protein. Computational chemistry techniques, such as molecular docking
and virtual screening , assess the binding affinity and stability of these generated
molecules, narrowing down the pool of candidates for further investigation [12].
Machine learning and artificial intelligence play a pivotal role in de novo drug de-
sign, as they can analyze vast datasets of known drug–target interactions, enabling the
development of predictive models that guide the creation of novel compounds [13]. By
learning from historical successes and failures, these algorithms become increasingly
proficient at proposing molecules with higher probabilities of therapeutic efficacy and
lower toxicity. Furthermore, de novo drug design embraces the principles of medicinal
chemistry to fine-tune the properties of candidate molecules. Researchers aim to opti-
mize factors like drug-likeness, bioavailability, and pharmacokinetics to ensure that the
resulting compounds possess the desired characteristics for clinical use. This iterative
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