4 research outputs found
Fusion of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors
Cyclin dependent kinases play a central role in cell
cycle regulation which makes them a promising target with multifarious
therapeutic potential. CDK2 regulates various events of the eukaryotic
cell division cycle, and the pharmacological evidence indicates that
overexpression of CDK2 causes abnormal cell-cycle regulation, which
is directly associated with hyperproliferation of cancer cells. Therefore,
CDK2 is regarded as a potential target molecule for anticancer medication.
Thus, to decline CDK2 activity by potential lead compounds has proved
to be an effective treatment for cancer. The availability of a large
number of X-ray crystal structures and known inhibitors of CDK2 provides
a gateway to perform efficient computational studies on this target.
With the aim to identify new chemical entities from commercial libraries,
with increased inhibitory potency for CDK2, ligand and structure based
computational drug designing approaches were applied. A druglike library
of 50,000 compounds from ChemDiv and ChemBridge databases was screened
against CDK2, and 110 compounds were identified using the parallel
application of these models. On <i>in vitro</i> evaluation
of 40 compounds, seven compounds were found to have more than 50%
inhibition at 10 μM. MD studies of the hits revealed the stability
of these inhibitors and pivotal role of Glu81 and Leu83 for binding
with CDK2. The overall study resulted in the identification of four
new chemical entities possessing CDK2 inhibitory activity
Computationally Guided Identification of Novel <i>Mycobacterium tuberculosis</i> GlmU Inhibitory Leads, Their Optimization, and in Vitro Validation
<i>Mycobacterium tuberculosis</i> (Mtb) infections are
causing serious health concerns worldwide. Antituberculosis drug resistance
threatens the current therapies and causes further need to develop
effective antituberculosis therapy. GlmU represents an interesting
target for developing novel Mtb drug candidates. It is a bifunctional
acetyltransferase/uridyltransferase enzyme that catalyzes the biosynthesis
of UDP-<i>N</i>-acetyl-glucosamine (UDP-GlcNAc) from glucosamine-1-phosphate
(GlcN-1-P). UDP-GlcNAc is a substrate for the biosynthesis of lipopolysaccharide
and peptidoglycan that are constituents of the bacterial cell wall.
In the current study, structure and ligand based computational models
were developed and rationally applied to screen a drug-like compound
repository of 20 000 compounds procured from ChemBridge DIVERSet
database for the identification of probable inhibitors of Mtb GlmU.
The in vitro evaluation of the in silico identified inhibitor candidates
resulted in the identification of 15 inhibitory leads of this target.
Literature search of these leads through SciFinder and their similarity
analysis with the PubChem training data set (AID 1376) revealed the
structural novelty of these hits with respect to Mtb GlmU. IC<sub>50</sub> of the most potent identified inhibitory lead (5810599)
was found to be 9.018 ± 0.04 μM. Molecular dynamics (MD)
simulation of this inhibitory lead (5810599) in complex with protein
affirms the stability of the lead within the binding pocket and also
emphasizes on the key interactive residues for further designing.
Binding site analysis of the acetyltransferase pocket with respect
to the identified structural moieties provides a thorough analysis
for carrying out the lead optimization studies
Exploring Derivatives of Quinazoline Alkaloid l‑Vasicine as Cap Groups in the Design and Biological Mechanistic Evaluation of Novel Antitumor Histone Deacetylase Inhibitors
l-Vasicine is a quinazoline alkaloid with an electron dense
ring and additional functionalities in its structure. Employing target
oriented synthesis (TOS) based on in silico studies, molecules with
significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule,
i.e., <b>4a</b>, which contained 3-hyroxypyrrolidine as a cap
group and a six carbon long aliphatic chain as a linker was found
to inhibit HDACs. <b>4a</b> showed more specificity toward class
I HDAC isoforms. Also <b>4a</b> was found to be less cytotoxic
toward normal cell lines as compared to cancer cell lines. <b>4a</b> inhibited cancer cell growth and induced cell death by various mechanisms.
However, <b>4a</b> was found to induce cell death independent
of ROS generation, and unlike many natural product based HDAC inhibitors, <b>4a</b> was found to be nontoxic under in vivo conditions. Importantly,
we for the first time report the possibility of using a 3-hydroxypyrrolidine
cap for the synthesis of HDAC inhibitors with good potency
Design of Novel 3‑Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model
In
the present study, a novel series of 3-pyrimidinylazaindoles
were designed and synthesized using a bioinformatics strategy as cyclin-dependent
kinases CDK2 and CDK9 inhibitors, which play critical roles in the
cell cycle control and regulation of cell transcription. The present
approach gives new dimensions to the existing SAR and opens a new
opportunity for the lead optimizations from comparatively inexpensive
starting materials. The study led to the identification of the alternative
lead candidate <b>4ab</b> with a nanomolar potency against CDK2
and CDK9 and potent antiproliferative activities against a panel of
tested tumor cell lines along with a better safety ratio of ∼33
in comparison to reported leads. In addition, the identified lead <b>4ab</b> demonstrated a good solubility and an acceptable in vivo
PK profile. The identified lead <b>4ab</b> showed an in vivo
efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models
with a TGI (tumor growth inhibition) of 90% without any mortality
growth inhibition in comparison to reported leads