Computational assessment of clerodane-type furano-diterpenoids from Tinospora crispa: A potential source for anticancer lead compounds.

Tinospora crispa, a plant with widespread use in ethnomedicine, has several extracts as well as phytoconstituents that have been reported to possess anticancer properties. Clerodane-type furano-diterpenoids from this genus of plants show promise as anticancer agents, although only a few of these have been assayed in vitro. 38 clerodane-type furano-diterpenoids from T. crispa were assayed computationally against 13 common anticancer macromolecular targets. The assayed ligand library displayed higher binding affinities than the respective controls in six of the thirteen anticancer macromolecular targets. Binding affinity values that were higher than the respective controls were obtained for two ligands against BRCA1, for four against CDK9/Cyclin T1, for two against C-ROS1, for thirty-seven against EGFR, for three against MEK 1-kinase, and for one against STAT3. Many of these ligands displayed greater binding affinity values than the respective controls against multiple macromolecules. Notable among these are tinocrispide (against BRCA1, C-ROS1, EGFR and MEK1), tinosporol C (against CDK9/Cyclin T1 and MEK1-kinase), crispene E (against BRCA1 and CDK9/Cyclin T1) and (5R,6R,8S,9R,10R,12S)-15,16-Epoxy-2-oxo-6-O-(β-D-glucopyranosyl)-cleroda-3,13(16),14-trien-17,12-olid-18-oic acid methyl ester (against BRCA1 and EGFR). The top scoring compounds of each macromolecule were subjected to molecular dynamics simulations, and the obtained protein-ligand complexes were observed to be stable for all macromolecules except EGFR. The ligand library was mostly predicted to be soluble, but GI absorption was predicted to vary. A few were predicted to be carcinogenic, immunotoxic, and/or cytotoxic. Overall, the clerodane-type furano-diterpenoids from T. crispa show encouraging results in in-silico studies and may be considered for further modification and lead development.