Background: The drug response varies from person to person. The possibility for the drugs to move to a large number of bio molecular targets and lack of personalization are the major reasons for this. The multi targeting of drugs and resulted drug resistance and side effects can be minimized by designing and developing personalized drugs. Retro metabolic design strategy helps in generating promising molecules with less toxicity and side effects.
Methods: In the development of personalized drugs, PARP inhibitors have been identified as powerful anticancer drug molecules controlling BRCA1 mutations for breast cancer. However, the effect of most of these PARP inhibitors has been increased while using a combination of PARP inhibitors and drugs preventing the alkylation possibility of DNA like chlorambucil. The Retro metabolic Drug Design (RMDD) template has been taken from metabolite of chlorambucil. In the present work, the possibility of making analogs of metabolites of chlorambucil as soft drugs in PARP1 inhibitor for controlling BRCA1 mutations has been excavated. As an added advantage, the molecules seem to have a direct interaction with mutated BRCA1 protein molecules also.
Results: The designed molecules seem to be more personalized and their drug likeness is on a par with FDA approved drug for breast cancer subject to further in vivo and clinical evaluation. The approach has been identified as a promising technique for designing personalized anti-cancer drugs.
Conclusion: The people with the genetic signatures, rs28897696 are more prone to breast cancer resulted by the BRCA1 mutation. For the PARP inhibition analysis, Human ARTD1 (PARP1) catalytic domain in complex with inhibitor Rucaparib (4RV6) has been considered. The inhibitors of PARP1 and BRCA1 have been designed in the retrometabolic manner from metabolites of chlorambucil and active/ inactive metabolites present in human body. The evolved molecules, 8-(5-acetyl-2-hydroxyphenoxy)-4-amino-3-hydroxy-5-methyloctanoic acid, 4-amino-3-hydroxy-9-(4-hydroxy-3-methoxyphenyl)-5,5-dimethyl-9-oxononanoic acid and 8-(5-acetyl-2-hydroxyphenoxy)-4-amino-3-hydroxy-5,5-dimethyloctanoic acid are found to be promising anti-breast cancer drugs with comparatively low side effects and more personalization subject to further in vivo and clinical evaluations.
Keywords: BRCA-1, chemical drug delivery systems, effective drug response, personalized drugs, retro-metabolic design, soft drug.
P. M. Iyer, P. Kumar, S., Shanmugam, K., and P. K. Krishnan Namboori, “Retrometabolic approach for designing personalized anti- cancer drug molecules for controlling breast cancer resulted by BRCA1 mutations”, Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics), vol. 14, no. 1, pp. 56 - 64, 2016.