ARCIMS 26
in
Sunday 2025-10-19 17:32
Design and evaluation of Torcetrapib, Dalcetrapib, and Evacetrapib derivatives as inhibitors of CETP enzyme via scaffold hopping method
Soroush Rajabi Moghaddam 1 ℗, Saghi Sepehri 2 ©
Abstract
According to WHO, cardiovascular disease (CVD) is regarded as the most lethal event in all healthcare settings with a life cost of approximately 18 million annually. Hyperlipidemia is a term which refers to the condition in which the serum levels of LDL, cholesterol, triglyceride, and VLDL experience higher stages than normal threshold and this can pave the road for many serious diseases. It is believed that hyperlipidemia is the major cause of CVDs, so targeting and inhibiting it sounds like a rational method. Cholesteryl ester transfer protein (CETP) is an enzyme which is responsible for transforming HDL to LDL and it seems that this enzyme can theoretically support the progress of lipid-related disorders including CVDs. Developing CETP inhibitors can expand our ability of combatting CVDs by elevating HDL levels, and it may also prevent other metabolic disorders due to its protective effects. Scaffold hopping is one of the techniques which is used in medicinal chemistry to design drugs that are more potent and can bind stronger than the mother molecule to their target via changing the structure based on chemical similarities. One of the methods which we can apply in scaffold hopping is to replace moieties that are used in the drug’s structure bioisosterically to boost the pharmacological effect, improve potency, and enhance synthetic accessibility. Applying both computational methods and scaffold hopping can lead us to safer compounds with more potency, better binding, and higher stability. In this research, we have selected three drugs (Evacetrapib, Dalcetrapib, and Torcetrapib) and by using CADD techniques and utilizing scaffold hopping method, we want to structurally modify these drugs and evaluate the inhibitory activity of the designed compounds against CETP enzyme. We hope that our ultimate compounds will lead us to new therapeutic agents to tackle hyperlipidemia and CVDs.
Keywords: Molecular Docking, Molecular Dynamics, CETP, Scaffold Hopping
