121 research outputs found
Prodrugs for Masking Bitter Taste of Antibacterial Drugs - A Computational Approach
DFT calculations for the acid-catalyzed hydrolysis
of several maleamic acid amide derivatives revealed that
the reaction rate-limiting step is determined on the nature of
the amine leaving group. Further, it was established that
when the amine leaving group was a secondary amine,
acyclovir or cefuroxime moiety the tetrahedral intermediate
formation was the rate-limiting step such as in the cases of
acyclovir ProD 1- ProD 4 and cefuroxime ProD 1- ProD 4.
In addition, the linear correlation between the calculated and
experimental rates provided a credible basis for designing
prodrugs for masking bitter taste of the corresponding parental
drugs which have the potential to release the parent
drug in a sustained release fashion. For example, based on
the DFT calculated rates the predicted t1/2 (a time needed for
50 % of the reactant to be hydrolyzed to products) for
cefuroxime prodrugs, cefuroxime ProD 1- ProD 4, were
12 min, 18 min, 200 min and 123 min, respectively
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes
is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal
Chemistry section of the journal Molecules. In these Editorials, we highlight in brief reports (of about
one hundred words) a number of recently published articles that describe crucial findings, such as the
discovery of novel drug targets and mechanisms of action or novel classes of drugs, which may inspire
future medicinal chemistry endeavors devoted to addressing prime unmet medical needs
A Novel Mathematical Equation For Calculating The Number of ATP Molecules Generated From Sugars In Cells
Adenosine triphosphate (ATP) is critical for all life from the simplest
to the most complex. All organisms from the microscopic to humans
utilize ATP as the source for their primary energy currency. This
manuscript describes a novel method to calculate the number of ATP
molecules generated from the consumption of any sugar (having 3-7
carbons). This calculation method based on the oxidation states of the
sugar’s carbons. The time needed to calculate the number of ATP
molecules by this method is less than 2 minutes whereas that required
by the current (regular) method is many hours and even days in some
cases. In addition, the current method requires drawing all biochemical
processes that the sugar undergoes upon its cellular respiration
(oxidation) while our method described herein does not
Overview on the Recent Drugs Delivery Approaches
This review provides the reader a concise overview of
the different biological barriers that hinder the delivery of
therapeutic agents through membranes, such as intestinal mucosa,
Brain Blood Barrier (BBB), and mediators of transport such as
efflux transporters and etc., and the approaches for overcoming
such barriers. The approaches discussed in this review include:
utilizing natural occurring transporters to deliver drugs
specifically to their targets, nucleoside analogues delivery, CYPactivated
prodrugs that target drugs to the liver, modification of
passive diffusion by efflux pumps, intestinal transporters such as
PEPT1 and GLUT1, Carrier Mediated Transport (CMT) systems
for transporting nutrients, vitamins or hormones into the central
nervous system, tissue selective drug delivery, administration of
an exogenous enzyme to reach the tumor site which is followed
by systemic administration of non-toxic prodrugs (ADEPT,
GDEPT and VDEPT), enzymes involve in the bioconversion of
ester-based prodrugs for activation (hydrolysis) of prodrugs to
their active forms, brain targeted Chemical Delivery Systems
(CDS), amino acid prodrugs to improve oral bioavailability,
sustained drug delivery and intravenous drug delivery.
In addition, Receptor-Mediated Transcytosis (RMT) for
efficacious delivery of Nano particles through the intestinal
mucosa and BBB, and the prodrug chemical approach based on
intra molecularity to deliver anti-cancer drugs is discussed
The prodrug approach in the era of drug design
Prodrugs are inactive precursors of an active drug designed to
be bioconverted (activated) post administration with the main
aim of improving the pharmacokinetic properties of the parent
drug. Prodrugs have been successful for a longtime.
Sulfasalazine, one of the earliest prodrugs, reaches the colon
and is metabolized by bacteria into two active metabolites:
sulfapyridine and 5-aminosalicylic acid (5-ASA). Sulfasalazine
was approved for use in the USA in 1950 and still is considered
first-line treatment in autoimmune conditions such as Crohn’s
disease and ulcerative colitis [1]. It has been demonstrated
that the prodrug approach has reached vast success in the
past few years. It is estimated that around 10% of all marketed
drugs are prodrugs, 20% of small molecular weight drugs
approved between 2000 and 2008 were prodrugs, and
between 2008 and 2017 the share of prodrugs in the drug
market was 12% [2].
Various strategies are employed in the prodrug approach.
The most common of which is making a prodrug susceptible
to abundant enzymes by functionalization with a group that
can be cleaved to produce the active form of the drug. The
prodrug approach to drug optimization offers chemical stability
such as an inactive oral prodrug can be stable in the
gastrointestinal tract and only be bioconverted by CYP450 in
the liver, plasma, or GIT mucosal esterase, or other enzymes.
Examples of this include phosphate groups which are susceptible
to alkaline phosphatase, ester groups which are susceptible
to esterases, and carbamates or amidine groups which
are susceptible to amidases. Newer strategies include pegylation,
which is used to increase cellular uptake, and dimer
prodrugs, which are cleaved to two active moieties.
Also, prodrugs can be used as precursors in biological
conversion pathways, as is the case with L-dopa, a prodrug
of dopamine. L-dopa crosses the blood-brain barrier through
L-type amino acid transporter-1 and is metabolized by aromatic
amino acid decarboxylase to active dopamine in the
CNS. Targeted prodrugs have also been explored in oncology
in order to minimize side effects and improve the tolerability
of chemotherapy [3].
Prodrugs are also used to increase the duration of action of
medicines, acting as chemical sustained release forms.
Lisdexamfetamine dimesylate is an inactive prodrug of amphetamine used mainly in the treatment of attention deficit
hyperactivity disorder (ADHD). The prodrug is hydrolyzed by
red blood cells to L-lysine and active d-amphetamine. The
duration of action of lisdexamfetamine is 12 h [4] compared
to that of instant release amphetamine, which is 3-6 h.
In cardiovascular medicine, prodrugs have been successful.
Older prodrugs such as angiotensin-converting enzyme inhibitors
(ACEi) are considered cornerstones in the management
of hypertension. ACE inhibitors are dicarboxyl ester prodrugs
converted to their active -rilat form by liver esterase (such as
enalapril and enalaprilat). The exceptions for this are lisinopril
and captopril which are not prodrugs, and fosinopril, which is
a phosphonic acid prodrug hydrolyzed by liver and GIT
mucosa esterases. Newer prodrugs, such as dabigatran etexilate
and prasugrel (Table 1), are anticoagulants indicated for
the treatment and prevention of blood clotting.
Prodrugs of nucleoside analogs are used to improve pharmacokinetic
properties such as intestinal permeability and oral
absorption [15]. For instance, valacyclovir and valganciclovir
are valine ester prodrugs of acyclovir and ganciclovir, respectively,
target intestinal oligopeptide transporter aiming to
improve the oral absorption of the parent drug.This paper was not funded
Computationally Designed Enzyme Models to Replace Natural Enzymes in Prodrug Approaches
The striking efficiency of enzyme catalysis has inspired many
organic chemists to explore enzyme mechanisms by studying certain
intra molecular processes such as enzyme models which proceed faster
than their intermolecular counterparts. This research brings about the
important question of whether enzyme models will replace natural
enzymes in the conversion of prodrugs to their parental drugs.
Enzymes are mandatory for the inter conversion of many prodrugs
to their parental drugs. Among the most important enzymes in the
bioconversion of prodrugs are amides (ex. trypsin, chymotrypsin,
elastase, carboxypeptidase, and aminopeptidase) and ester-based
prodrugs (ex. paraoxonase, carboxylesterase, acetylcholinesterase
and cholinesterase). Most of these enzymes are hydrolytic enzymes,
however, non-hydrolytic enzymes, including all cytochrome P450
enzymes, are also capable of catalyzing the bioconversion of ester and
amide-based prodrugs [1].The author would like to acknowledge funding by the German Research
Foundation (DFG, ME 1024/8-1)
Prodrugs from Serendipity to Design by Computational Chemistry Methods
Imagination is more important than
knowledge when knowledge is limited and can
not solve important questions. Inventiveness in
the drug design has been clumsiness in quality
and quantity. This may be due to the ineptness
and incapability of medicinal chemists to
comprehend biochemistry and biology issues.
On the other hand, biochemists, biologists, and
pharmaceutical chemists do not possess the
expertise to make complex organic entities.
Hence, a team comprising of all expertise is a
must to invoke a novel drug
Newly Developed Prodrugs and Prodrugs in Development; an Insight of the Recent Years
Background: The design and development of prodrugs is the most common and e ective
strategy to overcome pharmacokinetic and pharmacodynamic drawbacks of active drugs. A respected
number of prodrugs have been reached the drugs market throughout history and the recent years
have witnessed a significant increase in the use of prodrugs as a replacement of their parent drugs
for an e cient treatment of various ailment. Methods: A Scan conducted to find recent approved
prodrugs and prodrugs in development. Results: Selected prodrugs were reported and categorized in
accordance to their target systems. Conclusions: the prodrug approach has shown many successes and
still remains a viable and e ective approach to deliver new active agents. This conclusion is supported
by the recent approved prodrugs and the scan of clinical trials conducted between 2013–2018.Funding: This research received no external funding.
Acknowledgments: The authors would like to thank Al-Quds University-Scientific Research O ce for covering
the publication fees for this review article
Computer-Assisted Design for Paracetamol Masking Bitter Taste Prodrugs
It is believed that the bitter taste of paracetamol,
a pain killer drug, is due to its hydroxyl group. Hence, it is
expected that blocking the hydroxy group with a suitable
linker could inhibit the interaction of paracetamol with its
bitter taste receptor/s and hence masking its bitterness.
Using DFT theoretical calculations we calculated proton
transfers in ten different Kirby’s enzyme models, 1–10. The
calculation results revealed that the reaction rate is linearly
correlated with the distance between the two reactive
centers (rGM) and the angle of the hydrogen bonding (α)
formed along the reaction pathway. Based on these results
three novel tasteless paracetamol prodrugs were designed
and the thermodynamic and kinetic parameters for their
proton transfers were calculated. Based on the experimental
t1/2 (the time needed for the conversion of 50% of the
reactants to products) and EM (effective molarity) values
for processes 1–10 we have calculated the t1/2 values for the
conversion of the three prodrugs to the parental drug,
paracetamol. The calculated t1/2 values for ProD 1–3 were
found to be 21.3 hours, 4.7 hours and 8 minutes,
respectively. Thus, the rate by which the paracetamol
prodrug undergoes cleavage to release paracetamol can be
determined according to the nature of the linker of the
prodrug (Kirby’s enzyme model 1–10). Further, blocking
the phenolic hydroxyl group by a linker moiety is believed
to hinder the paracetamol bitterness.The Karaman Co. is thanked for support of our
computational facilities. Special thanks are also given to Angi
Karaman, Donia Karaman, Rowan Karaman and Nardene Karaman
for technical assistance
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