Optimization of Lead Structures

A lead is only the starting point in developing a new drug. Potency, specificity, and duration of action must be optimized while minimizing side effects and toxicity. The structure of a compound is determined by its pharmacophore, which is responsible for target binding. Its binding groups enhance potency and biological activity, its lipophilicity is responsible for transport and distribution, and the groups to be cleaved or modified are responsible for the release of the active form. Several approaches can be used to modify the chemical structure of a lead, but optimization is multifactorial due to the highly correlated influences of the changes attempted. Bioisosteric functional group replacement tries to replace groups on a given scaffold with sterically and electronically related groups that maintain activity but improve other drug properties. Me-too research attempts to modify a competitor’s lead structures to create off-patent analogs with improved properties. If there is no change in activity, increasing the size of a molecule, adding chiral centers, and increasing the rigidity of the molecule will usually improve selectivity, while eliminating chiral centers, increasing flexibility, and decreasing size will make a drug less selective. The spectrum of activity of a compound can be tailored by even small structural changes that modulate affinity, transport, distribution, or metabolism. As a result, a given class of compounds can be active in very different therapeutic indications. The conversion of agonists to antagonists does not follow clear-cut rules, but increasing the size and attachment of hydrophobic groups such as aromatic rings often shifts the profile. The more polar a drug is, the less it can penetrate lipid membranes and the lower the absorption. On the other hand, specific transporters can support penetration. Prolongation of the duration of action is usually achieved by replacing metabolically labile groups with more stable isosteres, introducing more branching groups, blocking metabolically labile positions on aromatic rings with F or Cl, or exchanging L- for D-amino acids with simultaneous reversal of amide bonds. Molecular databases can be screened to identify other scaffolds or substitution patterns that alternatively represent a given pharmacophore. In the early stages of drug development, unwanted binding to plasma proteins, anti-targets such as the hERG ion channel, or preferential binding, inhibition or activation of transcription factors or metabolizing cytochrome P450 enzymes can be investigated and potentially avoided. Appropriate tuning of the thermodynamic binding profile may be essential to optimize binding affinity and provide a drug with the required target-specific properties. Similarly, interaction kinetics, which determine the on/off rates or residence times of binding, are critical for designing drugs with optimal pharmacological profiles. https://sn.pub/tts2en