Steroid derivatives are attractive scaffolds in drug discovery due to their structural rigidity and favorable physicochemical properties; however, they have consistently shown poor efficacy as antimalarial agents, and the molecular basis of this limitation remains unclear. This project aims to elucidate the reasons behind the weak antimalarial activity of steroid derivatives by integrating quantum chemical calculations, classical molecular simulations, and structure-based drug design (SBDD). Quantum mechanical studies are employed to analyze electronic properties, charge distribution, and reactivity descriptors of steroid scaffolds, while molecular docking and molecular dynamics simulations are used to evaluate binding modes, interaction stability, and dynamic behavior with key Plasmodium falciparum targets. Comparative analyses with established antimalarial compounds are conducted to identify critical structural and physicochemical shortcomings, such as suboptimal electrostatic complementarity, limited hydrogen bonding, steric constraints, or unfavorable solvation effects. Based on these insights, rational structure-based optimization strategies are proposed to modify steroid derivatives and enhance their predicted antimalarial potential, ultimately providing mechanistic understanding and design principles for improving scaffold performance in antimalarial drug discovery. 

Ryanodine Receptor 1 (RyR1) is a critical calcium-release channel involved in skeletal muscle excitation–contraction coupling and has been implicated in several neuromuscular and metabolic disorders, making it a promising therapeutic target. This project employs an integrated computational approach to characterize RyR1 at the molecular level and evaluate its druggability using structure-based drug design methodologies. Molecular modeling, docking, and molecular dynamics simulations are applied to investigate ligand-binding sites, conformational stability, and key protein–ligand interactions, while complementary quantum mechanical analyses are used to refine binding energetics and electronic contributions. The study aims to identify critical structural features governing RyR1 modulation and to generate rational design insights for the development of selective and effective RyR1-targeted therapeutics.