Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar 470003, MP, India.
Department of Chemical Technology, University of Calcutta, Kolkata 700009, WB, India.
Comput Biol Chem. 2017 Apr;67:213-224. doi: 10.1016/j.compbiolchem.2017.01.004. Epub 2017 Jan 11.
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 K=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; K 0.443μM 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.
生育控制是一个全球性的热点问题，旨在调节人口过剩和维持生态平衡。本研究采用计算机模拟方法探索一种非甾体类先导化合物作为避孕药物，以避免甾体类似物引起的多种禁忌症。从 Piper betle Linn. 中分离得到的 Aristolactam 类化合物 Piperolactam A 对雌激素和孕激素受体具有结合亲和力，分别为-8.9 和-9.0Kcal/mol（抑制常数 K=0.294μM 和 0.249μM），甚至大于已报道的拮抗剂如 Rohitukine 和 OrgC（结合亲和力-8.7 和-8.4Kcal/mol；K 0.443μM 和 0.685μM）。结合位点探索显示，Piperolactam A 与受体的氢键结合更多（His 524、Leu 346、Thr 347），而 Rohitukine 和 OrgC 则更少（Leu 718），这一点通过分子动力学模拟得到了进一步证实。该化合物具有药物特性，符合 Lipinsky 五规则，且毒性降低，如心脏毒性、肝毒性、致突变性和生态毒性。内分泌干扰组学和随后的对接引导分子模拟表明，Piperolactam A 与核受体（特别是 hERG 和细胞色素 P450）的结合亲和力较弱，结合概率较低。高的 Caco-2 渗透率表明该药物具有更高的生物利用度，因此具有更好的治疗效果。
