NovaLead Pharma Pvt Ltd.

Inspired from natural product isoliquiritine, an O‐glucoside and the corresponding aglycon chalcone, isoliquiritigenin (ISL), several C‐glucosylated chalcones and dihydrochalcones have been synthesized and evaluated for aldose reductase (AR) inhibition activity, for the first time. The initial inputs from molecular docking studies were also encouraging. Claisen‐Schmidt condensation reaction between 4‐C‐glucosylated benzaldehyde, a key building block developed during the synthetic efforts and acetophenones enabled convenient access to the targeted compounds in good yields. Excellent AR inhibition has been observed with C‐glucosylated ISL with IC50 value of 21 µM. This is similar to the chalcone ISL, displaying IC50 of 19 µM. In the light of limited aqueous solubility of ISL, the observed AR inhibition with C‐glucosylated ISL, gains importance. Additionally, the studies have revealed significance of the oxygenation pattern on the aromatic residue and paved way for the identification of few more new compounds with equally promising AR inhibition.

Mono-hydroxylated polychlorinated biphenyls (OH-PCBs) are found in human biological samples and lack of data on their potential estrogenic activity has been a source of concern. We have extended our previous in silico 2D QSAR study through the application of advance techniques such as docking and 3D QSAR to gain insights into their estrogen receptor (ERα) binding. The results support our earlier findings that the hydroxyl group is the most important feature on the compounds; its position, orientation and surroundings in the structure are influential for the binding of OH-PCBs to ERα. This study has also revealed the following additional interactions that influence estrogenicity of these chemicals (a) the aromatic interactions of the biphenyl moieties with the receptor, (b) hydrogen bonding interactions of the p-hydroxyl group with key amino acids ARG394 and GLU353, (c) low or no electronegative substitution at para-positions of the p-hydroxyl group, (d) enhanced electrostatic interactions at the meta position on the B ring, and (e) co-planarity of the hydroxyl group on the A ring. In combination the 2D and 3D QSAR approaches have led us to the support conclusion that the hydroxyl group is the most important feature on the OH-PCB influencing the binding to estrogen receptors, and have enhanced our understanding of the mechanistic details of estrogenicity of this class of chemicals. Such in silico computational methods could serve as useful tools in risk assessment of chemicals.

14‐3‐3 Proteins bind phosphorylated sequences in proteins and regulate multiple cellular functions. For the first time, we show that pure recombinant human 14‐3‐3 ζ, γ, ε and τ isofoms hydrolyze ATP with similar Km and kcat values. In sharp contrast the sigma isoform has no detectable activity. Docking studies identify two putative binding pockets in 14‐3‐3 zeta. Mutation of D124A in the amphipathic pocket enhances binding affinity and catalysis. Mutation of a critical Arg (R55A) at the dimer interface in zeta reduces binding and decreases catalysis. These experimental results coincide with a binding pose at the dimer interface. This newly identified function could be a moon lighting function in some of these isoforms.