Peptidomimetic drug design against epilepsy:

Design and Development of Novel TRH Derivatives as Antiepileptic Compounds: In search of potent anti-epileptic compounds (AEC), we designed and screened a library of thyrotropin-releasing hormone (TRH) derivatives based on informatics and chemistry-driven approaches. Specifically, homology modeling, molecular docking, and pharmacokinetics predictions were used for virtual screening of peptidomimetics for their selective binding to thyrotropin-releasing hormone receptor‑2 (TRHR‑2), a drug target for AECs, and improved pharmacokinetics. We developed and implemented a study protocol which combined the use of in silico, in vitro, and in vivo studies iteratively to identify novel THR analogues (RSC advances 2015, Euro. J. Med. Chem. 2016, Bio. Med. Chem. 2015). The identified compounds were several folds selective towards TRHR‑2. This protocol can be easily transferred to other peptidomimetics drug design studies.

Intestinal transport mechanism of anti-epileptic compounds:

Mechanistic Insights into PepT1-Mediated Intestinal Transport of Antiepileptic Compounds: A previously unexplored atomic‑level mechanism of intestinal transport of selected antiepileptic compounds was studied. We built and reported the first 3D model of the 12 TM helix intestinal transporter protein, Peptide transporter 1 (PepT1). Based on homology modeling, molecular docking and MD simulation of PepT1‑ligand complexes, the mechanism of intestinal permeability was successfully correlated with in vitro Caco-2 cell permeability studies and structural modifications were suggested to get high permeability through this transporter protein. We concluded that hydrophobic forces between protein and ligands were attributed to the intestinal permeability of compounds (Mol. Pharm. 2012, J. Mol. Recog. 2014).

Publications:

• Chhuttan L Meena, Avinash Thakur, Prajwal P Nandekar, Shyam S Sharma, Abhay T Sangamwar, Rahul Jain; Synthesis and biology of ring-modified l-Histidine containing thyrotropin-releasing hormone (TRH) analogues, 2016, European journal of medicinal chemistry, Volume 111, Pages 72-83, IF: 4.519.
• Chhuttan L Meena, Shubdha Ingole, Satyendra Rajpoot, Avinash Thakur, Prajwal P Nandekar, Abhay T Sangamwar, Shyam S Sharma, Rahul Jain; Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice, 2015, RSC Advances, Volume 5 (70), Pages 56872-56884, IF: 3.108.
• Chhuttan L Meena, Avinash Thakur, Prajwal P Nandekar, Abhay T Sangamwar, Shyam S Sharma, Rahul Jain; Synthesis of CNS active thyrotropin-releasing hormone (TRH)-like peptides: Biological evaluation and effect on cognitive impairment induced by cerebral ischemia in mice, 2015, Bioorganic and Medicinal Chemistry, Volume 23 (17), Pages 5641-5653, IF: 2.93.
• Pravin Bagul, Kailas S Khomane, Siddharth S Kesharwani, Preeti Pragyan, Prajwal P Nandekar*, Chhuttan Lal Meena, Arvind K Bansal, Rahul Jain, Kulbhushan Tikoo, Abhay T Sangamwar; Intestinal transport of TRH analogs through PepT1: the role of in silico and in vitro modeling, 2014, Journal of Molecular Recognition, Volume 27 (10), Pages 609-617, IF: 2.175.
• Kailas S Khomane, Prajwal P Nandekar, Banrida Wahlang, Pravin Bagul, Naeem Shaikh, Yogesh B Pawar, Chhuttan Lal Meena, Abhay T Sangamwar, Rahul Jain, K Tikoo, Arvind K Bansal; Mechanistic insights into PEPT1-mediated transport of a novel antiepileptic, NP-647, 2012, Molecular Pharmaceutics, Volume 9 (9), Pages 2458-2468, IF: 4.44