Abstract

STRUCTURE-BASED DESIGN OF TAFAMIDIS ANALOGUES FOR TRANSTHYRETIN STABILIZATION: IN-SILICO STUDY

*Pranali J. Sabale, Vaishnavi S. Pawar, Sandhya P. Kadam, Dr. Prakash D. Jadhav, Prerana J. Sabale

Abstract

The progressive condition known as transthyretin amyloidosis (ATTR) is brought on by the misfolding and aggregation of transthyretin (TTR), which causes organ dysfunction, particularly in the heart and peripheral nerves. Tafamidis is an oral benzoxazole derivative that inhibits the development of amyloid by stabilizing the TTR tetramer and preventing its dissociation into monomers. The pharmacokinetic, toxicological, and molecular interaction profiles of tafamidis and its derivatives were assessed in this work using an in-silico method. Protein targets from the Protein Data Bank (PDB IDs: 4HIQ and 4HIS) were used for molecular docking studies using PyRx, and ADMET characteristics were predicted using pkCSM. Tafamidis has a substantial binding affinity (-6.4 kcal/mol), according to the data, although its ADMET characteristics are limited. The 2-(3,5-dichlorophenyl)-6-(3,5- difluoro-4-hydroxyphenyl) benzo[d]oxazol-5-ol (Fig.no. 9) derivative was noteworthy for its balanced pharmacokinetic behaviour, good absorption, blood-brain barrier permeability, and similar binding affinity (~−8.3 kcal/mol). These results imply that structural alteration can preserve biological activity while improving drug-likecharacteristics. Overall, our study emphasizes how crucial it is to combine ADMET prediction with molecular docking in order to optimize tafamidis derivatives in ATTR therapy.

Keywords: Tafamidis, Transthyretin Amyloidosis, ADMET prediction, Structure-based drug designs, Molecular docking, In-silico study.