Computational Modelling in Drug Disposition

School of Medical and Allied Sciences
Course Code : Course Name:
COMPUTATIONAL MODELLING IN
DRUG DISPOSITION
MADE BY: SHIVANG DHOUNDIYAL

ADMISSION NUMBER:21SMAS2020011
GALGOTIA UNIVERSITY
Name of the Faculty: Program Name:

INDEX
• Introduction
• Modeling Technique
• Drug Absorption (Solubility and Intestinal Permeation)
• Drug Distribution
• Drug Excretion
• Active Transport (P-gp, BCRP, Nucleoside Transporters,
hPEPT1, ASBT, OCT, OACP, BBB-Choline Transporter)
• Current Challenges and future Directions
INTRODUCTION
Historically, drug discovery has focused almost exclusively on efficacy
and selectivity against the biological target.As a result, nearly half of drug
candidates fail at phase II and phase III clinical trials because of the
undesirable drug pharmacokinetics properties, including absorption,
distribution, metabolism, excretion and toxicity (ADMET).The pressure
to control the escalating cost of new drug development has changed the
paradigm since the mod-1990s.To reduce the attrition rate at more
expensive later stages, in vitro evaluation of ADMET properties in the
early phase of drug discovery has widely adopted.
Many high-throughput in vitro ADMET
property screening assays have been
developed and applied successfully.
Fueled by the ever-increasing
computational power and significant
advances of in silico modeling algorithms,
numerous computational programs that
aim
. at modeling ADMET properties have
emerged.
A comprehensive list of available
commercial ADMET modeling software
has been provided till date.
Modelling Technique
There are two approaches:
The quantitative approaches represented by pharmacophore modeling and flexible docking

studies investigate the structural requirements for the interaction between drugs and the
targets that are involved in ADMET processes. These are especially useful when there is an
accumulation of knowledge against certain target. For example, a set of drugs known to be
transported by a transporter would enable a pharmacophore study to elucidate the
minimum required structural features for transport.Three widely used automated
pharmacophore perception tools are DISCO (DIStance Comparisons), GASP (Genetic
Algorithm Similarity Program) and Catalyst/HIPHOP.
The qualitative approaches represented by quantitative structure-activity

relationship (QSAR) and quantitative structure-property relationship (QSPR)
studies utilize multivariate analysis to correlate molecular descriptors with
ADMET-related properties.A diverse range of molecular descriptors can be
calculated based on the drug structure. Some of these descriptors can be
calculated based on drug structure.It is essential to select the right mathematical
tool for most effective ADMET modeling. Sometimes it is necessary to apply
multiple statistical methods and compare the results to identify the best
approach.
Drug Absorption
Because of its convenience and good
patient compliance, oral administration is
the most preferred drug delivery form. As a
result, much of the attention of in silico
approaches is focused on modeling drug
oral absorption, which mainly occurs in the
human intestine.In general, drug
bioavailability and absorption is the result of
the interplay between drug solubility and
intestinal permeability.
) Solubility
drug generally must dissolve before it can be absorbed from the
estinal lumen.
measuring a drug's logP value (log of partition coefficient of
mpound between ) and its melting point, one could indirectly
timate solubility using "general solubility equation".
predict the solubility of compound even before synthesizing it, in
co modeling can be implemented.
ere are mainly two approaches to model solubility. One is based on
e underlying physiological processes, and the other is an empirical
proach. The dissolution process involves the breaking up of solute
om its crystal lattice and the association of the solute with solvent
olecules.
mpirical approaches, represented by QSPR, utilize multivariate analysis
identify correlations between molecular descriptors and solubility.
b) Intestinal Permeation
Intestinal permeation describes the ability of drugs to cross the intestinal mucosa separating the gut
lumen from the portal circulation.It is an essential process for drugs to pass the intestinal membrane
before entering the systemic circulation to reach their target site of action.The process involves both
passive diffusion and active transport.It is a complex process that is difficult to predict solely based on
molecular mechanism.As a result, most current models aim to simulate in vitro membrane permeation
of Caco-2, MDCK or PAMPA, which have been a useful indicator of in vivo drug absorption.
Drug Distribution
- Distribution is an important aspect of drug's pharmacokinetic profile.The
structural and physiochemical properties of a drug determine the extent of
distribution, which is mainly reflected by three parameters:
- 1. volume of distribution (Vd)

- ,2. plasma-protein binding (PPB) and
- 3. blood-brain barrier (BBB) permeability.
Volume of Distribution (Vd)

Vd is a measure of relative partitioning of drug between plasma and tissue,
an important proportional constant that, when combined a drug is a major
determinant of how often the drug should be administered.However,
because of the scarcity of in vivo data and complexity of the underlying
processes, computational models that are capable of prediction Vd based
solely on computed descriptors are still under development
Plasma Protein Binding (PBP)

Drugs binding to a variety of plasma
proteins such as serum albumin, as
unbound drug primarily contributes to
pharmacological efficacy.The effect of PPB
is an important consideration when
evaluating the effective (unbound) drug
plasma concentration.The models
proposed to predict PBB should not rely on
the binding data of only one protein when
predicting plasma protein binding because
it is a composite parameter reflecting
interactions with multiple protein
Blood-Brain Barrier (BBB)
The BBB maintains the restricted extracellular environment in the central nerve system.The
evaluation of drug penetration through the BBB is an integral part of drug discovery and
development process.Again, because of the few experimental data derived from inconsistent
protocols, most BBB permeation prediction models are of limited practical use despite intensive
efforts.Most approaches model log blood/brain (logBB), which is a measurement of the drug
partitioning between blood and brain tissue.The measurement is an indirect implication of BBB
permeability, which does not discriminate between free and plasma protein-bound solute.
Drug Excretion
The excretion or clearance of a drug is quantified by
plasma clearance, which is defined as plasma volume
that has been cleared completely free of drug per unit
of time.Together with Vd, it can assist in the
calculation of drug half-life, thus determining the
dosage regimen.Hepatic and renal clearances are the
two main components of plasma clearance.No model
has been reported that is capable of predicting
plasma clearance solely from computed drug
structures.Current modeling efforts are mainly
focused on estimating in vivo clearance from in vitro
data.Just like other pharmacokinetic aspects, the
hepatic and renal clearance process is also
complicated by presence of active transporters.
Active Transporters
Transporters are an integral part of any ADMET modeling program because of

their presence on barrier membranes and the substantial overlap between their
substrates and many drugs.Unfortunately, because of our limited understanding
of transporters, most prediction programs do not have a mechanism to
incorporate the effect of active transport.However, interest in these transporters
has resulted in a relatively large amount of in vitro data, which in turn have
enabled the generation of pharmacophore and QSAR models for many of
them.These models have assisted in the understanding of the complex effects
of transporters on drug disposition, including absorption, distribution and
excretion.
Current Challenges and Future Direction

The major recent advancement in ADMET modeling is in elucidating the role and
successful modeling of various transporters.
Incorporation of the influence of these transporters in the current models is an ongoing
task in ADMET modeling.
Some commercial programs have already implemented the capability of modeling
active transport, such as recent version of GastroPlus (Simulation Plus,
Lancaster,CA), PK-Slim (Bayer Technology Services, Germany) and ADME/Tox WEB
(Pharma Algorithms, Toronto, Canada).
In the latter software, compounds are first screened against pharmacophore models of
different active transporters. The compound that fits these models is removed for
further predictions, which is based solely on physiochemical properties.
Not all pharmaceutical companies can afford the resources to generate their
own in-house modeling programs, so the commercially available in silico
modeling suites have become an attractive option.Some modeling programs
such as Algorithm Builder (Pharma Algorithms, Toronto, Canada) are offering
flexibility for costumers to generate their in-house models with their own
training set and the statistical algorithm of their choice.These trends will
accelerate the shift of model building from computational scientists to
experimental scientists.
References
► Ekins S, "Computer Applications in Pharmaceutical Research and Development",
(2006) John Wiley and Sons Inc., chapter 20, pp495-508>
Ekins S, Nikolsky Y and Nikolskaya T. Techniques: Application of systems biology to
absorption, distribution, metabolism, excretion and toxicity. Trends Pharmacol Sci
2005;26;202-9
►https://hemonc.mhmedical.com/content.aspx?
bookid=1810&sectionid=124489864(accessed in 13th May, 2018)
THANK YOU

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School of Medical and Allied Sciences

Course Code : Course Name:

MADE BY: SHIVANG DHOUNDIYAL

Name of the Faculty: Program Name:

There are two approaches:

The quantitative approaches represented by pharmacophore modeling and flexible docking

The qualitative approaches represented by quantitative structure-activity

- 1. volume of distribution (Vd)

Volume of Distribution (Vd)

Plasma Protein Binding (PBP)

Blood-Brain Barrier (BBB)

Transporters are an integral part of any ADMET modeling program because of

Current Challenges and Future Direction

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