Executive Summary : | This project aims to develop fixed dose combinations (FDCs) of anticancer drugs, focusing on complex diseases caused by genetic, environmental, and lifestyle factors. Combination therapy has gained attention in recent years due to increased medical adherence and patient compliance. For example, Entresto, an FDC of valsartan-sacubitril approved by the Us-FDA in 2015, reduces the risk of cardiovascular death and treatment of heart failure in adult patients. Combination therapy has shown higher response rates than monotherapies in treating cancer. searching for FDCs of already approved or investigational drugs saves cost and time due to their well-performed pharmacokinetic and safety profiles. New applications in FDCs can be assessed quickly in clinical trials, reducing the average time for FDA/EMA approval from approximately 14 to 5 years. To design and develop successful FDCs, a systemic screening of approved drugs followed by their likelihood of salt or cocrystal formation will be done using the pKa rule and computational technique. The computational technique for virtual screening of cocrystals uses molecular electrostatic potential surface (MEPs) calculations and surface site interaction points (ssIPs). A single list of H-bond parameters will be prepared for both components, and the feasibility of cocrystal formation will be predicted by calculating the energy difference between the interaction site pairing energies of the cocrystal and the two pure molecules. The proposal combines three areas: crystal engineering, mechenochemistry, and pharmaceutical chemistry to develop FDCs to overcome acquired resistance over monotherapy. |