Quinine Sulfate

There is growing research on the allosteric behaviour of proteins, including studies on allosteric mutations that contribute to human diseases and the development of allosteric drugs. Allostery also plays a key role in drug metabolism, an essential factor in drug development. However, population specific variations, particularly in 3D protein structures, remain understudied. This study focuses on CYP3A4, a key enzyme responsible for metabolizing over 50% of FDA-approved drugs and often linked to adverse drug reactions. Given the vast genetic diversity of Africa, we investigated 13 CYP3A4 alleles from African populations using post-molecular dynamics analyses, with 12 being single variations and one containing a double variation. Except for one, all allele variations were located away from the active site, suggesting allosteric effects. Our comparative analyses of reference and variant structures, through hydrogen bond interactions, dynamic residue network analysis and substrate channel dynamics, revealed notable differences at both global and residue levels. The *32-I335T variant showed the largest changes compared to the reference structure, while *3-M445T (near normal metabolizer) exhibited the least change, with other variants falling in between. The *32-I335T variant showed a distorted conformation in the radius of gyration, a distinct kink in the I helix with specific hydrogen bonds and altered channel patterns. The *12-L373F variant, associated with reduced metabolism of midazolam and quinine, showed increased rigidity in its vicinity, potentially interfering with catalytic activity. Our findings align with clinical and wet lab data, suggesting that our approaches could be applied to analyse variants without clinical evidence.