PhD Work

I have started my research career as doctoral fellow in computational chemistry by learning the theoretical methods for modeling the chemical systems. The journey was started with Molecular mechanics (MM), QSAR, docking and pharmacophore that later were implemented for vinyl sulphones, tubulin binders, ionic liquids, and vinca alkaloids modelling (reference attached in papers). In this course, some of the challenging bottlenecks of draggability criteria were also addressed in expectations of proposing molecular attributes-based filters against biological targets. Subsequently, after learning the computational basics and quantum mechanical methods (ab-initio and DFT), in particular; I have shifted to my Ph.D. research problem i.e., understanding the electronic, structural and biological properties of the calixarene derivatives.  Calix[n]arene or metacyclophanes [1n], are amongst the most versatile platforms that constitute an important and indispensable part of supramolecular architectures. In particular, oxacalix[4]arenes (OC), in which the methylene bridge replaced by an oxygen, hold additional recognition features. Motivating from the fact that knowledge of conformational behaviour is ideal for implementing and designing the oxacalixarenes, the conformational preferences of OC (cone, 1,3-alternate, partial cone and 1,2-alternate) were studied in gas and solvent phases at Density Functional Theory (DFT) level to unveil the energetics and conformational equilibrium. It was observed that the 1,3-alternate conformer was relatively more stable due to the presence of bridged oxygen that strengthen the cation pi and pi-pi interactions in this conformer. Furthermore, the fate of complexation and distribution of electrostatic potential with population analysis (NBO and mulliken); crucial for the analyte recognition were also examined. Similarly, we have appraised calix[4]tetrolarenes for the conformational energetics and examined the role of methyl substitution on the stability of varied conformers. We found that the conformational profile of calix[4]tetrolarene changes by incorporating –OMe group. Looking at the RMSD, it is clear that B97D and wB97XD functionals gave the most accurate result. Furthermore, NBO calculation demonstrated that reduction in charges at lower rim oxygens reduces the chances of hydrogen bonding. We concluded that upon substituting another –OMe group at ipso, para position; the conformational equilibrium changes from cone to 1,3-Alternate. Owing to the methoxy substitutions, anion binding study of these new molecules indicates their promising capability to bind Cl- and F- ions. This study has shifted our interest for anion recognition by one of the widely studied urea/thiourea scaffolds. We subsequently modelled urea/thiourea substituted calix[4]arenes for their binding with spherical (F -, Cl-, Br-, I-) and linear anions (N3-  and SCN-). This study uses the binding energies to address structural basis of anion binding and explains the molecular basis of interactions between the host-guest systems.  Using the available experimental information, we were able to conclude that thiourea substitutions with NH donor have better capability to stabilize the anions as compare to urea. However, everytime the strength of interaction is not the sole deciding criteria, rather structural orientation of macrocyclic motifs is also responsible for ranking hosts binding potentials. Therefore, in one of the host the favourable arrangement of steric features lead to deprioritize thiourea substituted calixarene. This study suggest that synergy of chemical functionality alongwith favourable orientation of supramolecule governs the selectivity/specificity host for particular guest.

In the scenario of host-guest system, guest-responsive structural changes were also studied by taking the calixpyrrole as the modelled system. Their complexes with lower alcohols were studied. In particular, this work describes molecular assembly behaviours and long-range cooperative effects that are mainly encoded by the charge polarising effects. A quantitative assessment was made for different alcohols by correlating the cooperative effects with the partial charges.

Knowing the host-guest binding principle, I have implemented this knowledge to design calixarene based host system (recognition pairs) for tyrosine kinase inhibitors (TKI’s). Specifically, the end-focus was to improve the bioavailability profile of these second generation TKI’s with the monomolecular drug carrier. In that course, functionalized calix[n]arene (n=4, 5, 6  and  8) via appended groups SO3H, tert-Butyl (t-Bu), iso-Propyl (i-Pr), COOH, C2H4OH, and C2H4NH2  were appraised for the formation of optimal complex with six  TKI’s (gefitinib, regorafenib and sunitinib, nilotinb,  lapotinib  and dasatinib). A total of 144 complexes were explored for the predominantly involved selective and dynamic interactions using the shape based fitting algorithms, electronic structure methods, MM-GBMV and MD simulations. From this study, we conclude that there is no apparent selectivity in the orientation and insertion mode for a particular calix[n]arene and TKI’s. It was found that more coordinating nature of the substituent at the upper rim yield the most stable complexes over the less coordinating substituents. Within our studied chemical space, calix[n]arenes with n = 6 and 8 are the most promising drug carriers owing to their ability to wrap around the TKI’s and thereby maximize non-bonded interactions. 

Other than that, I have also expand the landscape of my PhD work by studying the “turn off” fluorescence ability of functionalized calix[4]arene for the selective detection of analytes like pendimethalin (PM), N-methyl-p-nitroanilne (NMA), copper ion sensing and selective binding with cerium (III) ion. Also, molecular interaction were unveiled for the dye degradation by substituted calixarenes and their inability to reduced/stabilized metal salts.