Byline: Syed Kashif Zafar, Sadaf Iqbal, Majid Mumtaz, Syed Kashif Ali and Syed Tariq Ali
Summary: Natural products play a significant role in the design of anticancer drugs acting on DNA replication. Different classes of natural products include meroterpene, phenol, flavonoid and coumestan isolated from Psoralea corylifolia plant have been found active against cancer disease. DNA polymerase and topoisomerase are the important reported targets for cancer chemotherapy. In the present work, docking analysis of total fifteen different phenol-based (1-12) and furanocoumarin-based (13-15) natural products from P. corylifolia were studied against DNA polymerase [alpha]. The objective of this study was to find the potential binding residues of phenol-based inhibitors against DNA polymerase [alpha]. In the light of docking results, it can be suggested that crucial interactions of inhibitor's phenolic group with the amino acid residues of DNA polymerase [alpha] are responsible for their activity.
In particular, hydrogen bond interaction between phenol-based natural products with the carboxylate oxygen of Asp1004 residue is of prime importance as the mutated enzyme has no polymerase activity at all. Moreover, hydrophobic and I-I stacking interactions between phenol-based inhibitors and Tyr865, DG110, DG111, and DC11 side chains of DNA polymerase [alpha] are also observed which may play an additional role. It is further elucidated that furanocoumarin-based natural products did not show any significant interaction with the ASP1004 due to the absence of phenolic OH group. Docking results disclose the reason behind the activity of phenol-based and inactivity of furanocoumarin-based natural products against DNA polymerase [alpha].
Keywords: Psoralea corylifolia, Phyto-phenols, DNA Polymerase [alpha], Docking.
In drug discovery and drug development process, natural products play a significant role in the development of new lead compounds. As a result of fast escalation in the finding of molecular targets, these may be useful to the discovery of new tools for prevention, diagnosis and treatment of human diseases. Fruits of Psoralea corylifolia L. (Leguminosae) are important sources in Chinese and Indian folkloric medicine for the treatment of premature ejaculation, enuresis, knee pain, backache, pollakiuria, vitiligo, callus, psoriasis and alopecia . Different classes of natural products have been isolated from P. corylifolia which have been found as inhibitors of mammalian DNA replication . It is reported that natural products, inhibiting mammalian DNA replication are potentially useful for Cancer Chemotherapy . DNA polymerases and topoisomerases are enzymes that take part in DNA metabolism during mitosis such as replication, transcription, recombination, and chromosome segregation.
For this reason, these enzymes are important targets for the improvement of Cancer Chemotherapeutic agents [6-9].The human genome encodes 16 DNA polymerases (pols) that are involved to control cellular DNA synthesis . In the reported literature, eukaryotic cells have three replicative types: pols [alpha], I and Iu, plus mitochondrial pol I3, and about twelve repair types: pols ss, I, Iu, , n, I,, , K, I>>, u, and I and REV1 . For distinguishing pols, selective inhibitor of each pol is helpful for clarifying their biological and in vivofunction . Several inhibitors from natural products for DNA polymerases are under...