Articles written in Journal of Chemical Sciences

    • Dynamic ligand-based pharmacophore modeling and virtual screening to identify mycobacterial cyclopropane synthase inhibitors


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      Multidrug resistance in Mycobacterium tuberculosis (M. Tb) and its coexistence with HIV arethe biggest therapeutic challenges in anti-M. Tb drug discovery. The current study reports a Virtual Screening(VS) strategy to identify potential inhibitors of Mycobacterial cyclopropane synthase (CmaA1), an importantM. Tb target considering the above challenges. Five ligand-based pharmacophore models were generatedfrom 40 different conformations of the cofactors of CmaA1 taken from molecular dynamics (MD) simulationstrajectories of CmaA1. The screening abilities of these models were validated by screening 23 inhibitors and1398 non-inhibitors of CmaA1. A VS protocol was designed with four levels of screening i.e., ligand-basedpharmacophore screening, structure-based pharmacophore screening, docking and absorption, distribution,metabolism, excretion and the toxicity (ADMET) filters. In an attempt towards repurposing the existing drugsto inhibit CmaA1, 6,429 drugs reported in DrugBank were considered for screening. To find compounds thatinhibit multiple targets of M. Tb as well as HIV, we also chose 701 and 11,109 compounds showing activitybelow 1 μM range on M. Tb and HIV cell lines, respectively, collected from ChEMBL database. Thus, a totalof 18,239 compounds were screened against CmaA1, and 12 compounds were identified as potential hits forCmaA1 at the end of the fourth step. Detailed analysis of the structures revealed these compounds to interactwith key active site residues of CmaA1.

    • Temperature Dependence of the Stability of Ion Pair Interactions, and its Implications on the Thermostability of Proteins from Thermophiles


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      An understanding of the determinants of the thermal stability of thermostable proteins is expected to enable design of enzymes that can be employed in industrial biocatalytic processes carried out at high temperatures. A major factor that has been proposed to stabilize thermostable proteins is the high occurrenceof salt bridges. The current study employs free energy calculations to elucidate the thermodynamics of the formation of salt bridge interactions and the temperature dependence, using acetate and methylguanidium ionsas model systems. Three different orientations of the methylguanidinium approaching the carboxylate grouphave been considered for obtaining the free energy profiles. The association of the two ions becomes more favorable with an increase in temperature. The desolvation penalty corresponding to the association of the ionpair is the lowest at high temperatures. The occurrence of bridging water molecules between the ions ensures that the ions are not fully desolvated, and this could provide an explanation for the existence of internal watermolecules in thermostable proteins reported recently. The findings provide a detailed picture of the interactions that make ion pair association at high temperatures a favorable process, and reaffirm the importance of saltbridges in the design of thermostable proteins.

    • Quantum mechanical investigation of the nature of nucleobase-urea stacking interaction, a crucial driving force in RNA unfolding in aqueous urea


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      Urea-assisted denaturation of protein and RNA has been shown to be a valuable tool to study their stabilities and folding phenomena. It has been shown that stacking interactions between nucleobases and urea are one of the driving forces of denaturation. In this study, the ability of urea to form unconventional stacking interactions with RNA bases is investigated by performing high-level quantum calculations (RI-MP2/aug-ccpVDZ level) on a few thousands of model systems. Four systems were considered based on the RNA nucleobases (GUA, ADE, CYT, and URA) for the investigation. For each system, a set of models were designed to study the role of hetero-atoms/groups of the nucleobases on stacking interactions with urea moiety with respect to every possible pair. Several plane-parallel complexes were generated with urea on top of aromatic systemsto exhaustively study all possible factors for urea-nucleobases stacking interactions. Energy decomposition analysis (EDA), atoms in molecules (AIM) and natural bond orbital (NBO) analysis were performed to gain better insights on non-covalent stacking interactions. Dispersion component was found to be heavily stabilizing,while the EHF was found to be repulsive for all the four systems indicating lack of hydrogen bonding (HB) type interactions and presence of dispersion type interactions. Amide and carbonyl groups of urea molecule werefound to play a major role in favourable stacking interactions. We demonstrate that along with functional groups present on the nucleobases, the orientation of urea molecules plays a vital role in stabilizing the urea-nucleobasenon-covalent interactions. The proposed study quantifies and provides a comprehensive theoretical description of urea nucleobase unconventional stacking interactions which helps to unravel urea driven RNA unfoldingmechanism

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