Abstract:
Heteroatom-heteroatom bonds are usually regarded and eliminated as 'undesirable' chemical moieties during drug development due to their low bond dissociation energies (BDE) and they are vulnerable to electrophilic attack by proteins in biochemical assays. Over 100 marketed drugs contain these 'undesirable' moieties demonstrating that not all of them are undesirable. Therefore, establishing a theoretical 'safety level' for heteroatom-heteroatom BDE is helpful in defining drug-like chemical space to aid drug designers. This study is based on the calculations of heteroatom-heteroatom BDE for marketed drugs and non-drug compounds (i.e. benchmark compounds, normal compounds) by using quantum chemical software with the aid of the density functional theory (DFT) method. First, the relationship between experimental and theoretical BDE values were established from benchmark compounds at R2=0.8787. Then it was followed by calculations of energy differences between drugs and non-drug compounds which were separated into five bond groups. The statistical significant differences were observed from N-N and N-S groups but not for N-O, O-S and S-S groups which indicates that low BDE is not the main factor in why heteroatom-heteroatom compounds are excluded from drug development. A more plausible explanation is their electron rich nature which leaves them susceptible to electrophilic attack in biological systems.
