Pharmacoinformatics study of Piperolactam A from Piper betle root as new lead for non steroidal anti fertility drug development.
Fertility control is a burning problem all over the world to regulate population overflow and maintain ecological balance. This study is an in-silico approach to explore a non-steroidal lead as contraceptive agent in order to avoid several contraindications generated by steroidal analogues. Piperolactam A, an aristolactam isolated from Piper betle Linn. showed binding affinity towards estrogen and progesterone receptor as -8.9 and -9.0Kcal/mol (inhibition constant Ki=0.294μM and 0.249μM) respectively which is even larger than that of reported antagonists such as Rohitukine and OrgC (binding affinity -8.7 and -8.4Kcal/mol; Ki0.443μM and 0.685μM respectively). The binding site exploration displayed more hydrogen bonding of Piperolactam A (His 524, Leu 346, Thr 347) than Rohitukine and OrgC (Leu 718) with associated receptors which was further confirmed by molecular dynamics simulations. The drug-likeliness of the compound has been proved from its tally with Lipinsky's Rule of Five and lowered toxicity such as cardiac toxicity, liver toxicity, mutagenicity and ecological toxicity. Endocrine disruptome and later docking guided molecular simulations revealed that Piperolactam A has weaker binding affinity and/or lower probability of binding with nuclear receptors especially hERG and cytochrome P450. The high Caco-2 permeability suggested more bioavailability hence more therapeutic efficacy of the drug.
Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar 470003, MP, India.
Sk Abdul
SA
Amin
Department of Chemical Technology, University of Calcutta, Kolkata 700009, WB, India.
Plaban
P
Bhattacharya
Dr. B.C. Roy College of Pharmacy and Allied Health Sciences, Durgapur 713206, India. Electronic address: souvik_basak1@yahoo.com.
Souvik
S
Basak
Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar 470003, MP, India.
Shovanlal
S
Gayen
Department of Chemical Technology, University of Calcutta, Kolkata 700009, WB, India.
Ashis
A
Nandy
Department of Chemical Technology, University of Calcutta, Kolkata 700009, WB, India.
Achintya
A
Saha
D000818:Animals; D001665:Binding Sites; D002867:Chromones / Q000737:chemistry; D003271:Contraceptive Agents, Female / Q000737:chemistry* / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D000072237:ERG1 Potassium Channel / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000737:chemistry; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry* / Q000633:toxicity; D007527:Isoenzymes / Q000737:chemistry; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D031721:Piper betle; D010880:Piperidines / Q000737:chemistry; D011980:Receptors, Progesterone / Q000737:chemistry
C573233:5,7-dihydroxy-2-methyl-8-(4-(3-hydroxy-1-methyl)-piperidinyl)-4H-1-benzopyran-4-one; D002867:Chromones; D003271:Contraceptive Agents, Female; D000072237:ERG1 Potassium Channel; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D026121:Indole Alkaloids; D007527:Isoenzymes; C000606913:KCNH2 protein, human; D008024:Ligands; D010880:Piperidines; D011980:Receptors, Progesterone; C457227:piperolactam A; D003577:Cytochrome P-450 Enzyme System
ADMET study; Contraceptive activity; Molecular docking; Piper betle; Piperolactam A