Research Title: Synthesis, adenosine receptor binding and molecular modelling studies of novel thieno[2,3‐d]pyrimidine derivatives

Author: Balakumar Chandrasekarn, Published Year: 2018

Chemical Biology and Drug Design, 91

Faculty: Pharmacy

Abstract: A series of new molecules containing a thieno[2,3‐d]pyrimidine scaffold was synthesized and characterized by adopting an efficient synthetic scheme. The effect of a free or substituted amino group at 2‐position as well as an oxo‐group, imidazole or 1,2,4‐triazole ring at 4‐position of the scaffold on the affinity and selectivity towards adenosine receptors (ARs) was evaluated. Compounds 17–19 with a free amino group at 2‐position along with the presence of an imidazole/1,2,4‐triazole ring at 4‐position of the scaffold showed selective binding affinities for hA2A AR, whereas carbamoylation of the amino group at 2‐position (in the presence of an oxo‐group at 4‐position of the scaffold) increased the affinity and selectivity of certain compounds (7–10) for hA3 AR. Molecular dynamic simulation study of one of the most active compound 8 (Ki hA1 > 30 μm, hA2A = 0.65 μm, and hA3 = 0.124 μm) revealed the role of important amino acid residues for imparting good affinity towards hA3 and hA2A ARs. Molecular docking studies were carried out for other compounds using the crystal structure of hA2A AR and a homology model of hA3 AR to rationalize their structure–activity relationships. The molecular docking results were in agreement with the experimental binding affinity data of ARs.

Keywords: adenosine receptors binding homology modelling molecular docking molecular dynamics thieno[2,3‐d]pyrimidine

Research Title: Crystal structure of the Eg5-K858 complex and implications for structure-based design of thiadiazole-containing inhibitors

Author: Balakumar Chandrasekarn, Published Year: 2018

European Journal of Medicinal Chemistry , 156

Faculty: Pharmacy

Abstract: The thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design.

Keywords: 1,3,4-thiadiazoleK858 enantiomersEg5Antimitotic drugsEg5-K858 complexRational drug design

Research Title: Synthesis, anticancer evaluation, and molecular docking studies of some novel 4,6-disubstituted pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 (CDK2) inhibitors

Author: Balakumar Chandrasekarn, Published Year: 2018

Bioorganic Chemistry , 79

Faculty: Pharmacy

Abstract: A novel series of 4,6-disubstituted pyrazolo[3,4-d]pyrimidines (7–43) bearing various anilines at C-4 position and thiophenethyl or thiopentane moieties at C-6 position have been designed and synthesized by molecular hybridization approach. All the synthesized compounds were evaluated for in vitro CDK2/cyclin E and Abl kinase inhibitory activity as well as anti-proliferative activity against K-562 (chronic myelogeneous leukemia), and MCF-7 (breast adenocarcinoma) cell lines. The structure–activity relationship (SAR) studies revealed that compounds with thiophenethyl group at C-6 with mono-substituted anilines at C-4 exhibited better CDK2 inhibitory activity compared to alkyl group (thiopentane) at C-6 and di-substituted anilines at C-4 of the scaffold. In particular, compounds having 2-chloro, 3-nitro and 4-methylthio aniline groups at C-4 displayed significant enzymatic inhibitory activity against CDK2 with single digit micromolar IC50 values. The in silico molecular docking studies suggested possible binding orientation and the binding energies were in agreement with the observed SAR as well as experimental results. In addition, some of the synthesized compounds showed anti-proliferative effects against K-562 and MCF-7 cancer cell lines with IC50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization.

Keywords: Pyrazolo[3,4-d]pyrimidineCyclin dependent kinase inhibitorAnti-proliferative activityMolecular dockingGLIDE

Research Title: Design and synthesis of novel thiadiazole-thiazolone hybrids as potential inhibitors of the human mitotic kinesin Eg5

Author: Balakumar Chandrasekarn, Published Year: 2018

Bioorganic and Medicinal Chemistry Letters, 28

Faculty: Pharmacy

Abstract: A novel series of 1,3,4-thiadiazole-thiazolone hybrids 5a–v were designed, synthesized, characterized, and evaluated against the basal and the microtubule (MT)-stimulated ATPase activity of Eg5. From the evaluated derivatives, 5h displayed the highest inhibition with an IC50 value of 13.2 µM against the MT-stimulated Eg5 ATPase activity. Similarly, compounds 5f and 5i also presented encouraging inhibition with IC50 of 17.2 µM and 20.2 µM, respectively. A brief structure–activity relationship (SAR) analysis indicated that 2-chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed significantly to enzyme inhibition. An in silico molecular docking study using the crystal structure of Eg5 further supported the SAR and reasoned the importance of crucial molecular protein–ligand interactions in influencing the inhibition of the ATPase activity of Eg5. The magnitude of the electron-withdrawing functionalities over the hybrids and the critical molecular interactions contributed towards higher in vitro potency of the compounds. The drug-like properties of the synthesized compounds 5a–v were also calculated based on the Lipinski’s rule of five and in silico computation of key pharmacokinetic parameters (ADME). Thus, the present work unveils these hybrid molecules as novel Eg5 inhibitors with promising drug-like properties for future development.

Keywords: 1,3,4-Thiadiazole-thiazolone MT-stimulated ATPase of Eg5 Hybridization Knoevenagel condensation GLIDEADME prediction

Research Title: Copper‐Catalyzed Self‐Condensation of Benzamide: Domino Reactions towards Quinazolinones

Author: Balakumar Chandrasekarn, Published Year: 2018

European Journal of Organic Chemistry, 2018

Faculty: Pharmacy

Abstract: We herein report a simple and highly efficient microwave‐assisted, copper‐catalyzed and ligand‐free synthetic method for 2‐substituted 4(3H)‐quinazolinones as domino reaction. This reaction proceeds via self‐condensation of substrate (2‐bromo/iodo benzamide) in the presence of a strong base and copper catalyst. The substituted quinazolinones were obtained in one‐pot reaction by intramolecular cyclization (condensation) via Ullmann–type intermediate. Both the intermediates and quinazolinones were obtained in good yield and can be further used as building blocks for developing the potential novel drug‐like compounds.

Keywords: copper‐catalyzed and ligand‐free synthetic method

Research Title: Ligand- and structure-based in silico studies to identify kinesin spindle protein (KSP) inhibitors as potential anticancer agents

Author: Balakumar Chandrasekarn, Published Year: 2018

Journal of Biomolecular Structure and Dynamics , 36

Faculty: Pharmacy

Abstract: Kinesin spindle protein (KSP) belongs to the kinesin superfamily of microtubule-based motor proteins. KSP is responsible for the establishment of the bipolar mitotic spindle which mediates cell division. Inhibition of KSP expedites the blockade of the normal cell cycle during mitosis through the generation of monoastral MT arrays that finally cause apoptotic cell death. As KSP is highly expressed in proliferating/cancer cells, it has gained considerable attention as a potential drug target for cancer chemotherapy. Therefore, this study envisaged to design novel KSP inhibitors by employing computational techniques/tools such as pharmacophore modelling, virtual database screening, molecular docking and molecular dynamics. Initially, the pharmacophore models were generated from the data-set of highly potent KSP inhibitors and the pharmacophore models were validated against in house test set ligands. The validated pharmacophore model was then taken for database screening (Maybridge and ChemBridge) to yield hits, which were further filtered for their drug-likeliness. The potential hits retrieved from virtual database screening were docked using CDOCKER to identify the ligand binding landscape. The top-ranked hits obtained from molecular docking were progressed to molecular dynamics (AMBER) simulations to deduce the ligand binding affinity. This study identified MB-41570 and CB-10358 as potential hits and evaluated these experimentally using in vitro KSP ATPase inhibition assays.

Keywords: KSP inhibitors, pharmacophore modelling, CDOCKER, molecular dynamics, KSP ATPase enzyme inhibition

Research Title: Pharmacophore Development

Author: Balakumar Chandrasekarn, Published Year: 2019

Faculty: Pharmacy

Abstract: Computational modeling techniques have evolved as an essential tool for the design and discovery of novel drugs. A number of molecular modeling approaches have been developed based on either the three dimensional structure of proteins (e.g., homology modeling, molecular docking and molecular dynamics simulations) or the ligand (e.g., 3D-QSAR and pharmacophore modeling). Each of these approaches have different objectives and outcomes. 3D pharmacophore modeling is one of the crucial tools for the discovery of new drugs using in silico drug design and optimization that complements the structure-based approaches. Pharmacophoric features in the drug or lead structure are very essential for the pharmacological activity. A pharmacophore can be deduced either from the binding site of the target protein or a set of pharmacologically active ligands. A discourse on essentials of pharmacophore …

Keywords: Computational modeling techniques

Research Title: Protein/Peptide Drug Delivery Systems: Practical Considerations in Pharmaceutical Product Development

Author: Balakumar Chandrasekarn, Published Year: 2019

Faculty: Pharmacy

Abstract: Proteins and peptides are involved in a wide range of vital functions and processes in the body that are essential for life. Proteins and peptides also have various roles in pathological conditions such as cancer and diabetes. Therefore, the use of proteins and peptides as therapeutic agents is considered as an attractive approach to combating various diseases. However, the physicochemical properties of proteins and peptides make them challenging for exogenous administration, especially by the oral route of administration. Various protein/peptide drug delivery systems have been extensively investigated to overcome the problems associated with the exogenous administration of protein and peptide therapeutics. In this chapter, different approaches for the delivery of proteins and peptides are discussed including chemical modifications, absorption enhancers, carrier systems, and various other approaches.

Keywords: Protein delivery nanoparticle carriers absorption enhancers PEGylation

Research Title: Synthesis of 4, 6-disubstituted pyrazolo [3, 4-d] pyrimidine analogues: Cyclin-dependent kinase 2 (CDK2) inhibition, molecular docking and anticancer evaluation

Author: Balakumar Chandrasekarn, Published Year: 2019

Journal of Molecular Structure , 1176

Faculty: Pharmacy

Abstract: The cyclin-dependent kinases (CDKs) play a crucial role in cell cycle progression and are validated targets of cancer therapy. Pyrazolopyrimidines are versatile scaffolds, which have been exploited for developing potential anticancer agents. We herein report the synthesis and in vitro CDK2/cyclin E kinase inhibitory activity of 34 novel 4,6-disubstituted pyrazolo [3,4-d]pyrimidines (9a-9s, 13a-13h, 14a-14d, 15a-15c). The structure-activity relationship (SAR) studies revealed that compounds with thiopentane/thiophenethyl group at C-6 and heteroatom-containing bicyclic moiety (benzofuran) at C-4 exhibited good CDK2 inhibitory activity. Further, the binding energies obtained for the active compounds from in silico molecular docking studies with CDK2 were found to be in consonance with the observed SAR and experimental results. In addition, some of the synthesized compounds showed anti-proliferative activity against K-562 (chronic myelogenous leukaemia) and MCF-7 (breast adenocarcinoma) cell lines in micromolar ranges. Further, the cytotoxicity studies on CHO cell line revealed that all the compounds are non-toxic to normal cells and are safe. Thus, the research findings revealed the anticancer potential of 4,6-disubstituted pyrazolo [3,4-d]pyrimidine derivatives which could be further considered for lead optimization.

Keywords: Pyrazolo[3,4-d]pyrimidine Cyclin-dependent kinase inhibitor Anti-proliferative activity Molecular docking GLIDE

Research Title: Recent Advances in the In-silico Structure-based and Ligand-based Approaches for the Design and Discovery of Agonists and Antagonists of A2A Adenosine Receptor

Author: Balakumar Chandrasekarn, Published Year: 2019

Current Pharmaceutical Design, 25

Faculty: Pharmacy

Abstract: A2A receptor belongs to the family of GPCRs, which are the most abundant membrane protein family. Studies in the last few decades have shown the therapeutic applications of A2A receptor in various diseases. In the present mini-review, we have discussed the recent progress in the in-silico studies of the A2A receptor. Herein, we described the different structures of A2A receptor, the discovery of new agonists and antagonists using virtualscreening/ docking, pharmacophore modeling, and QSAR based pharmacophore modeling. We have also discussed various molecular dynamics (MD) simulations studies of A2A receptor in complex with ligands.

Keywords: A2A receptor; GPCR; MD simulations; in-silico; pharmacophore modeling; virtual screening.