PMC:7755033 / 87307-90484 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7755033","sourcedb":"PMC","sourceid":"7755033","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7755033","text":"3.9. Structure activity relationship (SAR)\nWS is known to harbor a wide variety of secondary metabolites having low MWs viz. terpenoids, flavonoids, tannins, alkaloids and resins. Withanolides, alkaloids, flavonoids and tannins are the major chemical constituents that include compounds of diverse chemical structures (Dhar et al., 2015; Kumar et al., 2015). Of these, withanolides are attributed with diverse and widely known biological activities. In the present study, most of the predicted pharmacological activity against the chosen biological target(s) was found to be associated with two main withanolides, viz. withanolide A and B, as well as withanone, a WS phytoconstituent with structural similarity to withanolide D. Nearly 40 naturally occurring withanolides have been reported till date comprising of C-28 steroidal lactone triterpenoids assembled on an integral or reorganized ergostane structure, in which C-22 and C-26 are oxidized to form a six-membered lactone ring (Jain et al., 2012). The withanolide backbone is chemically classified as 22-hydroxy ergostane-26-oic acid 26, 22-lactone (Mirjalili et al., 2009). The withanolides consist of several oxygen atoms and are thought to be synthesized via oxidation of all carbon atoms in a steroid nucleus.\nThe parent configuration of withanolides and ergostane-type steroids is one C-8 or C-9 side chain with an either six or five membered lactone or lactol ring. A carbon-carbon bond or oxygen bridge is responsible in attaching the lactone ring with the carbocyclic part of the molecule (Mirjalili et al., 2009). Withanolides have a varying distribution in the fruits and vegetative parts of the plant such as leaves, roots and stem (Sangwan et al., 2008). However, withanolides are mainly localized in the leaves, in low concentrations (0.001–0.5% of dry weight) which is the main drawback for their use as drugs. Geographical, environmental and seasonal factors as well as growth conditions are also known to contribute to modulation of the content of withanolides (Dhar et al., 2013).\nIn the present study, the differential binding kinetics obtained for withanolide A (C28H38O6), withanolide B (C28H38O5), withanolide E (C28H38O7) and withanone (C28H38O7) might be attributed to the varying number of oxygen atoms in their structures which might affect hydrogen bonding within the binding site of the target protein(s). Another explanation for differential SAR obtained for the above withanolides might be due to various kinds of structural rearrangements (A or B) involving oxygen substituents like bond scission, new bond formation, ring aromatization, etc. which help in formation of novel structural variants and compounds with novel structures (Figure 5) often described as modified withanolides or ergostane type steroids (Misico et al., 2011). The structural rearrangement as seen in withanolide A and B might be responsible for a better complementary fit of the phytoconstituent in the binding pocket of the target protein(s).\nFigure 5. Structural differences in Withanolide A (R1 = OH, R2 = H); Withanolide B (R1 = H, R2 = H); Withanolide E (5β, 6β–epoxy) and Withanone (17α–OH, R1 = H, 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