Computational
Evaluation of Drug-Likeness and ADME Properties of Pyrazole and Chalcone
Derivatives
Sudesh1*, Nitika Mor2, Dr. Pooja Ranjan3,
Manni Dutta4
1 Research Scholar, Department of Chemistry, Baba Mastnath University,
Rohtak, Haryana
sudedivyu50@gmail.com
2 Assistant Professor, Department of Chemistry, Baba Mastnath University,
Rohtak, Haryana
3 Assistant Professor, Department of Chemistry, Hindu Girls
College, Sonipat, Haryana
4 Department of Chemistry, Arya PG College, Panipat, Haryana
Abstract
The
pyrazole and chalcone derivatives are bioactive molecules that have
considerable therapeutic importance. In this study, 16 derivatives were
computationally studied using the software of Molinspiration, admetSAR, AI Drug
Lab, and vNN-ADMET to analyze their physicochemical properties, druglikeness,
and ADMET properties. The Lipinski Rule of Five, along with other druglike
filters, was used to screen compounds and identify potential oral medications.
Based on the analysis of these compounds compared to curcumin, which acted as
the reference molecule, a few compounds exhibited better absorption,
permeability, oral bioavailability, and metabolic stability. The toxicity
analysis also predicted good safety profiles for these molecules. Compound 11 emerged
as the compound with the best balance of pharmacokinetics and toxicity among
the studied compounds.
Keywords: Pyrazole
derivatives, Chalcone derivatives, ADMET prediction, Drug-likeness, Lipinski
rule of five, In silico screening, Pharmacokinetics, Toxicity assessment
INTRODUCTION
Because of their various therapeutic applications, pyrazoles and chalcones belong to two important groups of organic compounds which have received much attention in medicinal chemistry. Pyrazoles are heterocyclic compounds which contain nitrogen, whereas chalcones are natural compounds that are related to flavonoids and possess an α, β-unsaturated carbonyl system. The pharmacological activities of both compound types have been extensively investigated, and they continue to serve as important templates for new therapeutics development.
Computational
methods have emerged to be effective and cost-efficient instruments in drug
discovery of our modern age [1-3]. They help scientists to make predictions
about biological and pharmacological properties of drugs before carrying out
actual experiments. Thus, this kind of approach makes it possible to save much
time and money while conducting experiments and to make a preliminary analysis
of the properties of a compound. Moreover, in silico analysis allows
researchers to rapidly analyze many molecules and select promising leads.
There are
several computer-based approaches that enable us to evaluate drug-likeness and
pharmacokinetic characteristics of molecules. Calculation of molecular descriptors
and prediction of activity parameters belong to common uses of Molinspiration
[4]. One of the most popular criteria for assessing the drug-likeness of oral
medications based on molecular weight, lipophilicity, hydrogen bond donors, and
hydrogen bond acceptors are Lipinski's rule of five [5].
Finally,
many scientists apply such software as SwissADME, ADMETSar, AI Drug Lab, and
vNN-ADMET to predict absorption, distribution, metabolism, excretion, and
toxicity of chemical substances.
Pyrazoles
are five-membered heterocyclic rings with two nearby nitrogen atoms. While one
nitrogen atom mimics pyridine and functions as a proton acceptor, the other
nitrogen atom acts similarly to pyrrole by giving a proton. The amphoteric
nature of pyrazoles is facilitated by this special arrangement, which also
permits tautomerism and hydrogen-bonding interactions, which have a significant
impact on their physicochemical and biological characteristics [6]. The
pyrazole ring's substituent actions alter its pharmacological behavior and
reactivity [7].
The
molecular formula of chalcones is 1,3-diaryl-2-propen-1-one with two phenyl
rings connected through an α, β unsaturated carbonyl compound. As a
result of the highly conjugated nature of the molecule, chalcones can be chemically
modified to form new compounds that exhibit diverse biological activities.
Several reports suggest that chalcone derivatives possess antibacterial,
antioxidant, anti-inflammatory, anticancer, antimalarial, antileishmanial, and
antifungal activities [8-11].
However, having significant pharmacological properties of the pyrazoles and chalcones derivatives is not enough for the successful use of these substances as drugs. There should be good ADMET features, which are essential in developing a pharmaceutical agent. In fact, their usage as drugs might be limited because of low absorption, metabolic problems, insufficient bioavailability, or toxicity. Hence, evaluation of ADMET features becomes vital for the drug discovery process. Thus, using an efficient tool for the selection of the best compounds among others, with good ADME/T properties, can help develop effective and safe drugs.
For the assessment of drug-likeness and pharmacokinetics of a set of 16 pyrazole and chalcone derivatives, an in silico study was conducted.
METHODOLOGY
Construction of Pyrazoles and Chalcones library
The vast
spectrum of biological activities of pyrazoles and chalcones (two among many
bioactive substances) is the reason why they play an increasingly important
role in medicinal chemistry. Pyrazoles are five membered heterocycles with two
adjacent nitrogen atoms in 1,2 positions. Due to their unique structure,
pyrazoles are capable of exhibiting strong interactions with various biological
targets, hence providing a diverse range of applications in medicine [12].
Chalcones, on the other hand, contain an unsaturated carbonyl group linking two
aromatic rings. Due to this structure, they possess high biological activity.
Various derivatives of chalcones have been proven to exhibit a number of
biological activities, such as antibacterial, antioxidant, anti-inflammatory,
antimalarial, antileishmanial, antitumor, and antifungal activities [13-14].
The most promising compounds with favorable therapeutic characteristics
were found using a variety of screening criteria, such as Lipinski's rule of
five and ADMET prediction studies. Curcumin, a bioactive substance that occurs
naturally and has been shown to have therapeutic value, served as a benchmark
for comparing the outcomes. Finding possible pyrazole and chalcone compounds
with better pharmacokinetic behavior and improved safety profiles over the
traditional medication was the study's primary objective.
Probable Drug Properties
The Molinspiration web server, which is an application program based on Java that helps in calculation of chemical properties and predicting bioactivity, was utilized in determination of the drug likeness attributes of chalcone derivatives. Some of the critical physicochemical attributes included MW, topological polar surface area (TPSA), partition coefficient (mLogP), H-bond donor (HBD), H-bond acceptor (HBA), N-rotatable bonds (Nrotb), and molecular volume. In all cases of the studied chalcone compounds, the structure preparation of the chemicals involved either drawing out the actual structures of the molecules or entering SMILES notation of the molecules. Afterwards, the molecules were analyzed individually.
Table 1 : Physiochemical and Drug-Likeness Evaluation
Of 28 Compounds Using Molinspiration
ADME Properties
The
pharmacokinetic profile of a drug in a biological system is largely dependent
on ADME (absorption, distribution, metabolism, and elimination). It is
necessary that any potential therapeutic candidate should show favorable ADME
properties, so that it can be effective and safe. Some of the major
pharmacokinetic properties include aqueous solubility, human intestinal
absorption (HIA), P-glycoprotein (P-gp) inhibition, Caco-2 permeability, oral
bioavailability, plasma protein binding (PPB), BBB (blood-brain barrier)
permeability, and maximum recommended therapeutic dose (MRTD), which were
explored in this study for molecules showing compliance with the rule of five
formulated by Lipinski (Table 3). Several computational methods like ADMETSar,
AI Drug Lab, and vNN-ADMET were utilized to analyze and predict these
pharmacokinetics properties [15-16].
Lipinski’s rule of Five
Lipinski’s rule is a widely used guideline in drug design
that helps in predicting whether a compound is likely to possess good oral bioavailability
and suitable drug-like properties [17]
According to this rule, A compound should
have
v
Molecular weight ≤ 500 daltons.
v
Log P ≤ 5.
v
H-bond acceptors (N or O) ≤ 10.
v
Only 5 H-bond donors (-NH or -OH) are allowed
v
Only one violation is permitted
Molecular Weight
Molecular
weight is a crucial factor in medication design because it influences a
compound's absorption and permeability,. A possible medication candidate's
molecular weight should typically be less than 500 Da, per the Ghose rule and
Lipinski's Rule of Five. Higher molecular weight compounds frequently exhibit
low absorption and poor membrane permeability. Only five of the sixteen
chalcone derivatives examined had molecular weights within the permissible
range, and as a result, they were chosen for additional analysis.
mLogP (Octanol/Water Partition Coefficient)
A
compound's lipophilicity is indicated by its mLogP value, which is crucial for
membrane permeability, absorption, solubility, and distribution [18]. Compounds
with LogP values less than 5 are deemed appropriate for oral medication
development, under Lipinski's criteria. Five of the sixteen chalcone
derivatives had acceptable mLogP values and were chosen for additional
screening.
Hydrogen Bond Donors and Acceptors
Drug-target
interaction, solubility, and permeability are greatly influenced by hydrogen
bond donors (HBD) and hydrogen bond acceptors (HBA). Good oral bioavailability
is more likely to be exhibited by compounds with balanced HBD and HBA values.
According to Lipinski's Rule of Five, five chalcone derivatives in the current
investigation met the suggested threshold for both HBD and HBA.
Rotatable Bonds
Covalent
bonds not in rings that allow free rotation between atoms and contribute to the
overall flexibility of the molecule are referred to as rotatable bonds.
Flexibility is an important consideration because it influences factors such as
membrane permeability, oral bioavailability, binding affinity, and selectivity
for biological targets [19]. If the compound is too flexible, the stability and
effectiveness of the potential drug could be adversely impacted. In accordance
with Veber's rules and Lipinski's guidelines, molecules with fewer than ten
rotatable bonds are considered preferable for oral drug formulation. The rotatable
bonds in all the chalcone derivatives under consideration fell within the
acceptable limits.
ADME Profile of Selected Pyrazole and Chalcone
Derivatives
Absorption Profile
Caco-2 permeability, Human Intestinal Absorption (HIA), aqueous solubility, oral bioavailability, % absorption, and MDCK permeability were some of the parameters that were considered while evaluating the absorption of the selected chalcones [20]. As per the results obtained from AI Drug Lab and ADMETSar, all of the selected molecules had satisfactory absorption characteristics when compared with those of curcumin (Table 3). Compounds 1, 2, 8, 9, and 11 demonstrated excellent intestinal absorption with their HIA values being slightly higher than those of curcumin (i.e., between 73.63% and 74.81% for the selected compounds versus 73.18% for curcumin). Furthermore, compounds 1 and 2 exhibited very high percentage absorption (~100%) as predicted by ADMETSar, whereas compounds 8, 9, and 11 also displayed comparable absorption percentages (97%).
Table
2 : ( AI Drug Lab) ADME Profile
It is
worth noting that positive membrane permeability was verified through the
similarity of Caco-2 permeability for all the compounds tested to that of
curcumin. It should be noted that all the selected compounds demonstrated
improved oral bioavailability values; however, compound 9 had the highest oral
bioavailability percentage (50.08%), followed by compounds 8 and 11.
Furthermore, the positive membrane permeability of these selected compounds was
supported by the MDCK permeability results..
Distribution Profile
BBB
permeability, PPBR, volume of distribution (VDss), and inhibitor properties on
transporters were the parameters considered in the distribution study [21].
Compared with curcumin, all the selected derivatives were able to penetrate the
BBB better based on BBB permeability predictions by the two software packages.
While compound 1 displayed the highest BBB permeability value, compound 11 had
values similar to those of the conventional drug and would minimize any
possible side effects on the CNS. PPBR values for all the derivatives were
found to be within the normal limit, indicating balanced interaction with the
plasma protein. Although there was reduced PPBR for compounds 1 and 2, compound
8 had relatively high PPBR when compared to curcumin. Based on VDss values,
good distribution was seen in all the derivatives. Inhibitions on transporters,
specifically for drugs 8, 9, and 11, revealed moderate to high P-glycoprotein
inhibitions.
Metabolism Profile
The
combination of HLM, HRM, and UGT substrate properties was evaluated along with
CYP450 enzyme inhibition and substrate predictions [23]. Selected compounds had
considerable to high inhibition toward the CYP2C9 and CYP2D6 enzymes. Although
inhibition towards CYP3A4 was considered moderate in most of the derivatives,
compound 8 and 9 had better inhibition against CYP2C9 than curcumin. Compounds
8, 9, and 11 could have more metabolic stability than curcumin based on HLM and
HRM results. Moreover, compared to conventional drugs, selected compounds had
significantly low UGT substrates, suggesting less metabolite formation and
possibly increased biological effect. In conclusion, metabolism studies
suggested good metabolic stability and proper enzyme interaction of selected
chalcones.
Excretion Profile
Furthermore,
the analysis included excretion parameters like half-life, hepatic clearance,
microsomal clearance, and mean residence time (MRT). In comparison with
curcumin, compound 2, 8, 9, and 11 exhibited higher values of half-lives which
implied better retention inside the biological system. Among those four
compounds, 11 demonstrated the highest value of half-life, i.e., 63.28 hours.
Lower
values of hepatic clearance were seen among compounds 8, 9, and 11 compared
with curcumin, implying their better metabolic stability. In terms of the value
of MRT, the predicted result for each selected chemical was far less than the
value for curcumin which showed balanced distribution/elimination process.
Those findings can imply a prolonged effect of the selected compounds.
Toxicity Profile
Toxicity
testing was carried out using the Ames test, hERG blocker prediction, drug
induced liver injury (DILI) and LD50 test. It was found that Compound 1
exhibited a lower hERG probability of being an hERG blocker than curcumin,
which implies a decreased cardiotoxic potential. Compounds 8, 9, and 11 had
slightly increased hERG and Ames values; however, toxicity levels remained
within allowable limits.
Compound
11 displayed the smallest DILI score among all tested molecules, which means
its ability to induce hepatotoxicity is lower than that of curcumin and other
tested derivatives. All compounds showed safe toxicity levels and moderate
acute toxicity with LD50 scores comparable to the standard medication.
CONCLUSION
Out of the selected chalcone derivatives, compound
11 emerged as the most promising one for drug development upon considering the
entire spectrum of ADME/Tox properties. As compared with the traditional drug,
curcumin, compound 11 had a higher oral absorption rate, better
bioavailability, good distribution properties, longer half-life, better
metabolic stability, and less hepatoxicity. Compound 11 provided a relatively
balanced profile in terms of ADME/Tox parameters, despite the slightly better
bioavailability of compound 9. Therefore, compound 11 could be regarded as the
most promising drug for future study.