Main concern in drug designing is for:
Ans. c. Increasing number of interactions of drug with target protein (Ref: Rational Approaches to Improving Selectivity in Drug Design by David J. Huggins, Woody Sherman, and Bruce Tidor; J Med Chem. 2012 February 23; 55(4) : 1424-1444.Problems in Drug Designing:Traditionally, drug design has been pursued with the primary objective of finding a compound that binds with high affinity to a target of interest.Conceptually, the problem of designing for a particular selectivity profile is significantly more complex than designing for high affinity to a single target.The underlying problem is challenging because it is necessary to evaluate energy differences for each ligand binding to a panel of targets and decoys rather than to a single desirable target.Drug DesigningDesigning a drug with the appropriate balance of avoidance of undesirable targets (narrow selectivity) and coverage of one or more targets of interest (broad selectivity, also referred to as promiscuity) is a continual drug development challenge.In many cases this objective is attained through trial and error, but there are rational approaches that can guide the tuning of selectivity'.Traditionally, drug design has been pursued with the primary objective of finding a compound that binds with high affinity to a target of interest.Recently, considerable effort has been expended measuring off-target interactions with partners such as ion channels (including the Kv 11.1 potassium ion channel hERG),cytochrome P450s (CYPs), and other proteins that can lead to adverse side effects.Other considerations, such as family or subtype selectivity have gamed considerable attention for targets with homologues that bind to the same or similar native substrates.While it is most common to design away from interactions with undesirable proteins, in other cases it is desirable to hit a panel of targets.Promiscuity must itself be selective for a given subset of targets, and nonspecific binding is always undesirable.In general, there is a fine balance in designing the appropriate level of narrow and broad selectivity, and one must determine the design criteria for selectivity based on the relevant biological processes.Conceptually, the problem of designing for a particular selectivity profile is significantly more complex than designing for high affinity to a single target.The underlying problem is challenging because it is necessary to evaluate energy differences for each ligand binding to a panel of targets and decoys rather than to a single desirable target.Computational methods are of limited accuracy when predicting affinities of individual complexes: these difficulties are compounded when multiple relative affinities are required to accurately design appropriate specificities.This problem becomes increasingly more difficult if the proteins anchor ligands have significant flexibility, as the size of the search space increases enormously.Essentially, designing for selectivity is significantly more complex than designing for affinity for two reasons:Because of the multifactorial nature of the taskBecause of the inherent difficulty of considering all modes of relaxation with sufficient accuracy, particularly when ligands bind decoy receptors.
Decreasing binding affinity of drug to target protein
Increasing binding affinity of drug to non-target protein
Increasing number of interactions of drug with target protein
Decreasing the potency of the drug
Pharmacodynamics