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Sarwal Amita
✶
, Bharti Sunil, and T.V.S. Padmajyoti
5 Computational approaches
to the prediction of the blood–brain
distribution and design of targeted drugs
Abstract: The blood–brain barrier (BBB) is a highly selective barrier between the
brain and the rest of the body. To show the effect in CNS the therapeutic agent must
cross the BBB. Therefore it is important to predict the BBB permeability of the drugs.
Log BB (the concentration of the drug in the brain divided by the concentration in
blood) and log PS (permeability surface area product) are the two critical parameters
used for the prediction of BBB permeability. The evaluation of BBB permeability of a
drug by traditional methods is techni cally challenging, long-drawn-out, and expen-
sive. Computational approaches such as QSAR models, molecular dynamics (MD) tech-
niques, machine learning (ML) model, artificial neuronal network (ANN) model, etc.
are useful in predicting the BBB permeability drugs in a reliable quick and feasible
way. Software like Cerius2 and ACD/LogD Suite has be en used widely for predicting
permeability through BBB. Several invasive, noninvasive, and miscellaneous techni-
ques were developed for targeting drugs in the brain. The adaptation of software
tools like QbD and DoE helps in the screening and optimization of formulations, mak-
ing them promising vectors for brain targeting. The formulation of BBB targeting tech-
nologies is a very active field for research and development.
Keywords: Blood–brain barrier penetration, computational drug design, neurophar-
macokinetics, BBB permeability prediction, central nervous system-targeted therapies
5.1 Introduction
Brain diseases, such as Alzheimer’s, Parkinson’s, epilepsy, brain injuries, brain cancer,
neuroinflammation and stroke, affect a significant portion of the global population. The
treatment of these diseases is challenging due to the presence of the blood–brain bar-
rier (BBB), which covers the entire brain. The BBB serves as a protective barrier and
regulates the transport of nutrients, serum factors, and neurotoxins into the brain.
However, it also poses a major obstacle to the delivery of therapeutic drugs, limiting
their efficacy [1].
✶
Corresponding author: Sarwal Amita, University Institute of Pharmaceutical Sciences, Panjab
University, Chandigarh, India, e-mail: sarwalamita@gmail.com
Bharti Sunil, T.V.S. Padmajyoti, University Institute of Pharmaceutical Sciences, Panjab University,
Chandigarh, India
https://doi.org/10.1515/9783111208671-005
https://t.me/med1917
Under normal physiological conditions, molecules can only access the brain or cere-
brospinal fluid (CSF) through the capillary endothelial cells (ECs) or choroid plexus cells
via transcellular routes involving passive or active transport. Passive diffusion, particu-
larly for lipid-soluble (lipophilic) molecules with a molecular mass under 400–600 Da,
is the main pathway through the cells with tight junctions (TJs). Other molecules may
traverse the cells through various endogenous transport systems, including carrier-
mediated transport, receptor-mediated transport, or absorptive-mediated transport.
Essential nutrients like amino acids, glucose, carboxylic acids, and nucleosides can
diffuse into the brain via these transport systems. The receptor-mediated tran sport
mechanism facilitates the transport of macromolecules conjugated with surface re-
ceptor ligands such as transferrin, lactoferrin, and insulin [2–4].
Brain-targeted drug delivery systems offer better solutions to overcome the chal-
lenges posed by the BBB. They provide a means to deliver therapeutic agents directly
to the brain, bypassing the restrictive barrier and incr easing drug accumulation at
the site of action. By improving drug delivery to the brain, these systems have the
potential to revolutionize the treatment of various brain diseases, offering new hope
for patients worldwide [1].
Over 98% of central nervous system (CNS)-targeted therapeutic compounds fail to
reach the market due to their inability to cross the BBB. It is crucial to assess BBB
permeability early in drug discovery to exclude poor candidates and expedite promis-
ing ones. In vitro, in vivo, and in silico methods are used to evaluate BBB permeability
[5–7]. These models of drug brain penetration aim to predict the permeability of the
BBB using parameters such a s hydrogen bonding, lipid solubility, and molecular
weight. These models typically use log(BB) as an index of BBB permeability, where BB
represents the brain-to-blood drug concentration ratio at a specific time point, often
60 min after drug administration. By utilizing these computational models, research-
ers can estimate and assess the ability of a drug to cross the BBB and reach the brain.
The most reliable index of the BBB permeability is considered to be the permeability-
surface area, which is considered to be a prime factor. This measure, expressed in
units of μL min
−1
g
−1
, represents the unidirectional clearance of a substance from the
blood to the brain across the BBB. Unlike the log(BB) parameter, the permeability-
surface area product provides a more accurate assessment of the permeability of the
BBB by taking into account both the surface area available for transport and the rate
at which substances are cleared from the blood into the brain. It is considered a valu-
able metric for evaluating the ability of drugs or substances to penetrate the BBB and
reach the brain [8].
In this chapter, we primarily focus on discussing the recently developed computa-
tional models for the prediction of the blood–brain (BB) distribution of drugs and for
designing targeted drugs for the brain.
88 Sarwal Amita, Bharti Sunil, and T.V.S. Padmajyoti
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5.2 Barriers to brain-targeted drug delivery
5.2.1 Blood–brain barrier
The history of the BBB can be dated back to the late seventeenth century when Hum-
phrey Ridley first demonstrated the low permeability of small cerebral vessels com-
pared to peripheral microvessels. This was later rediscovered by Paul Ehrlich in 1885,
where he showed that the brain is isolated from the bloodstream. Max Lewandowski
confirmed Ehrlich’s conclusion and coined the term “bluthirnschranke,” which means
BBB in German. Edwin Goldman, a student of Ehrlich, further conf irmed the BBB’s
existence by demonstrating that only the brain and spinal cord could be stained by
injected dyes, while peripheral organs remained unstained. In 1922, Lina Stern named
the interface that separates the brain from the rest of the organism “barrière hémato-
encéphalique” in French, which was eventually shortened to BBB. The BBB’s existence
was no longer questioned by the late 1920s [9].
5.2.1.1 Components of BBB and their functions
5.2.1.1.1 Endothelial cells
ECs are specialized cells derived from the mesoderm that line the walls of capillaries.
In the brain, these cells exhibit unique characteristics compared to ECs found in other
vascular regions. Brain ECs display luminal/abluminal polarization, tight junctions,
junctional adhesion molecules (JAMs), and specific transport mechanisms to regulate
the movement of polar substances. They are rich in mitochondria, which play a cru-
cial role in ATP generation and maintaining ion gradients necessary for transport
functions. Brain ECs also possess distinct vascular metabolism, altering the physical
properties of substances and affecting their solubility, reactivity, and transport fea-
tures. The regulation of these unique characteristics is facilitated by pericytes and as-
trocytic endfeet close to the brain ECs [10–12].
The ECs in the brain are sealed by tight junctions, which are significantly closer
compared to those found in peripheral capillaries. This close arrangement restricts the
passive transmission of molecules into the brain, contributing to the high transendothe-
lial electrical resistance (TEER) of brain blood vessels. Endothelial-specific claudin fam-
ily members (Cldn) and occludin (Ocln) are the proteins responsible for forming tight
junctions. These proteins are connected to the actin cytoskeleton through the ZO family
(ZO1, −2, −3). Claudin 5 (Cldn5) is particularly important for TJ development and BBB
function. Occludin, on the other hand, regulates tight junctions and is connected to zon-
ula occludins protein 1 (ZO-1). Impairment in the regulation of these junctional proteins
can compromise BBB integrity, allowing systemic entry into the brain, and potentially
leading to swelling or neurotoxicity [12–14]. In addition to tight junctions, adherens
junctions stabilize cell-cell connections in the junctional area. JAMs, such as JAM-A,
5 Computational approaches to the prediction of the blood–brain distribution 89
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JAM-B, and JAM-C, are present in cerebral endothelial cells and play a role in the devel-
opment and maintenance of tight junctions [12].
5.2.1.1.2 Astrocytes
Astrocytes are abundant and versatile star-shaped cells in the CNS that guide neuron
migration and act as buffers for potassium and neurotransmitters. They have special-
ized endfeet covering the cerebral capillaries and are formed from radial glia during
late gestation. Astrocytes contribute to the function and maturity of the BBB through
potassium channels in their endfeet. Proper regulation of astrocyte function is crucial
for enhancing BBB function and reducing BBB disruption. During inflammation, astro-
cytes exhibit different phenotypes (A1 and A2), with A1 cells being harmful and A2 cells
promoting healing. Astrocyte association with blood vessels is essential for maintaining
BBB integrity, and astrocyte-derived factors can both disrupt and repair the BBB [12,
15, 16].
5.2.1.1.3 Pericytes
Brain capillary pericytes are positioned at the center between endothelial cells, astro-
cytes, and neurons. Their interactions with endothelial cells are crucial for the develop-
ment, growth, stability, and maintenance of the BBB. Pericytes exhibit high phagocytic
activity and contribute to the clearance of harmful substances. They also play a role in
controlling BBB permeability and cerebral blood flow. Dysfunction or absence of BBB
pericytes is implicated in the pathophysiology of various diseases associated with mi-
crovascular instability [12, 17, 18].
5.2.1.1.4 Microglia
Microglia are a type of neuroglia present throughout the brain and spinal cord. They
constitute approximately 5–20% of the total glial cell population in the brain tissue.
These cells play a crucial role in supporting nerve cells by p roviding immunity, en-
gulfing harmful foreign particles, repairing damaged brain tissue, and participating
in extracellular signaling. Emerging evidence suggests that activated microglia can
regulate the expression of tight junctions, thus enhancing the integrity and functional-
ity of the BBB. This highlights the importance of microglia in maintaining the integrity
of the BBB and supporting overall brain function [12, 19].
5.2.1.1.5 Basement membrane
The basement membrane (BM) plays a critical role in controlling the permeability of
the BBB. The BM connects cells, regulates intercellular communication, and manages
the barrier function by interacting with extracellular matrix (ECM) proteins. It con-
sists of various molecules such as collagen, nidogen, laminin, sulfate, proteoglycans,
and glycoproteins. The BM acts as an anchor for signaling events in the vasculature
90 Sarwal Amita, Bharti Sunil, and T.V.S. Padmajyoti
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and serves as a barrier, preventing the entry of chemicals and cells into the brain tis-
sue [20, 21].
5.2.2 Blood–cerebrospinal fluid barrier
The blood–CSF barrier (BCB) is the second barrier encountered by systemically ad-
ministered drugs before they can enter the CNS. The BCB regulates the exchange of
molecules be tween the CSF and the interstitial fluid of the brain parenchyma. It is
primarily located in the choroid plexus epithelium, which limits the passage of mole-
cules and cells into the CSF. The choroid plexus and the arachnoid membrane work
together as barriers between the blood and CSF. The arachnoid membrane, positioned
between the dura and pia on the external surface of the brain, forms a double-
layered structure. It is impermeable to hydrophilic substances and plays a passive
role in forming the BCB barrier through tight junctions. The choroid plexus actively
produces CSF and regulates molecule concentrations within it. It consists of highly
vascularized cauliflower-like masses of pia mater tissue that dip into pockets formed
by ependymal cells. The cells of the choroidal epithelium, which line the ventricles
and surround the choroid plexus, have microvilli on the CSF side, basolateral interdi-
gitations, and abundant mitochondria. While the capillaries of the choroid plexus
allow the free movement of small molecules through gaps between the endothelial
cells, the adja cent choroidal epithelial cells form tight junctions that prevent most
macromolecules from effectively passing into the CSF from the blood. However, these
epithelial-like cells offer lower resistance compared to cerebral endothelial cells. The
BCB is additionally fortified by an active organic acid transporter system in the cho-
roid plexus, which actively removes therapeutic organic acids present in the CSF,
such as penicillin, methotrexate, and zidovudine, and drives them into the blood. This
prevents their diffusion into the brain parenchyma. Moreover, inconsistencies exist
between the composition of the CSF and the interstitial fluid of the brain parenchyma,
suggesting the presence of a barrier known as the CSF–brain barrier. This barrier is
attributed to the insurmountable diffusion distances required for equilibration be-
tween the CSF and brain interstitial fluid. Therefore, even though a drug may enter
the CSF, it does not guarantee its penetration into the brain [22].
5.2.3 Blood–tumor barrier
Gliomas, primary brain tumors, grow and spread rapidly. Initially, tumor cells resem-
ble the BBB. However, as the tumor progresses, the BBB becomes damaged, leading to
the formation of the BB tumor barrier composed of new blood vessels that are distinct
from the BBB.
5 Computational approaches to the prediction of the blood–brain distribution 91
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One major obstacle is the heterogeneous distribution of microvasculature through-
out the tumor, leading to inconsistent drug delivery within the tumor interstitial space.
Additionally, as a tumor grows larger, the vascular surface area decreases, reducing the
exchange of blood-borne molecules. The increased intracapillary distance in larger tu-
mors also creates a greater diffusional requirement for drug delivery to neoplastic
cells. Furthermore, high interstitial tumor pressure and associated peritumoral edema
result in increased hydrostatic pressure in the normal brain parenchyma surrounding
the tumor. This can make the cerebral microvasculature in these adjacent regions less
permeable to drugs than the normal brain endothelium, resulting in exceptionally low
drug concentrations in the extratumoral interstitial space. Although brain tumors may
disrupt the BBB locally, these disruptions are also nonuniform [12, 23]. Figure 5.1 Repre-
sents various mechanisms of transportation across BBB.
5.3 Methods to assess drug permeability across
the BBB
The inability of CNS medicinal substances to pass the BBB prevents them from reaching
the market in over 98% of cases. To quickly identify potential candidates and exclude un-
suitable ones, it is critical to evaluate BBB permeability early in the drug discovery pro-
cess. BBB permeability is assessed using in vitro, in vivo, and in silico techniques. Some of
the in vitro and in vivo techniques are outlined in this section, along with their benefits
Absorptive-mediated
transcytosis
Receptor-mediated transcytosis
Passive transport
P-glycoprotein
Carrier-mediated transpor
t
Tight junction
Blood
Brain
Endothelial cell
Nucleus
Y
Y
Y
Figure 5.1: Represents various mechanisms of transportation across BBB.
92 Sarwal Amita, Bharti Sunil, and T.V.S. Padmajyoti
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