Meeramol C Chellappan, Soumya Vasu, Shriraam Mahadevan, M K Kathiravan, J Saravanan, Soniya Naik, Knolin K Thachil
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引用次数: 0
Abstract
Background: Protein Interacting with NIMA1 (PIN1) is a distinct enzyme, known as a peptidyl-prolyl cis-trans isomerase (PPIase), which catalyzes the cis-trans isomerization of amide bonds in proteins containing phosphoserine/threonine-proline (pSer/Thr-Pro) motifs, presenting a unique therapeutic opportunity for addressing multiple disorders.
Methods: A series of 140 thiazole compounds were created using the shape similarity technique with the intention of discovering effective PIN1 inhibitors with a new scaffold. The designed compounds were docked into the enzyme's ATP binding site, and the binding free energies for all docked conformations were calculated. The compounds were evaluated for their ADMET and drug-likeness properties. Following the identification of top candidates, molecular dynamics simulations were conducted to investigate the binding dynamics of the highest-scoring compound.
Results: Based on computational findings, sixteen compounds were identified as potential PIN1 inhibitors. Among the sixteen compounds, four (S8Ba, S8Bb, S8Bd, and S8Bd) exhibited the most favorable ADMET profiles and robust interactions with key PIN1 residues. Molecular dynamics simulations confirmed that S8Ba and S8Bd exhibited the most promising activity over 100ns.
Conclusion: The results corroborated the docking outcomes, validating the selected hits as potential PIN1 inhibitors. This breakthrough could influence the development of therapeutic leads for combating diabetes, cancer, and Alzheimer's disease.
期刊介绍:
Aims & Scope
Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.