Molecular modifications lead compounds

The lead compounds undergo careful studies in an effort known as lead optimization. At this point any remaining issues with metabolism, absorption, toxicity, and so on, are addressed through molecular modification. 

With the crystal structure in hand, structure-based modification of the parent lead compound has just started to provide newpep-tidomimetic structures with lower molecular weight and fewer hydrogen bonds (e.g., 45) (Fig. 15.211, opening ftirther avenues to pharmacologically useful compounds (100). 

In analog design, molecular modification of the lead compound can involve one or more of the following strategies ... 

The explicit/implicit solvent approach just described requires doing at least one simulation for each protein-ligand complex. Therefore, it is still difficult to examine the binding of a large number of compounds to a receptor. However, if one focuses on a small subset of chemical space around a lead compound, one can adopt the same approximations as described earlier in free energy calculations so that simulations on the reference systems alone can be used to predict the effects of making many modifications on a lead compound. In these calculations, no molecular dynamics simulation needs to be performed on the derivatives of a lead compound. Instead, snapshots of the reference simulations are modified... 

Bioprecursors do not imply a temporary linkage between the active principle and a carrier group, but result from a molecular modification of the active principle itself. This modification generates a new compound, which is a substrate for metabolizing enzymes, leading to a metabolite that is the expected active principle. This approach exemplifies the active metabolite concept in a provisional way (e.g. sulindac, fenbufen, acyclovir, losartan). 

In the drug discovery process, a promising compound is referred to as a lead. The lead is a compound that demonstrates some desirable therapeutic or pharmacological characteristics, but at the same time, it may also show some undesirable effects like toxicity or poor absorption. Medicinal chemists use multiple techniques to identify leads that could be suitable for molecular modification in order to amplify the desirable characteristics and to eliminate, or minimize to an acceptable level, the undesirable characteristics. When the lead compound has been properly modified to get all the desirable characteristics of an active therapeutic agent, it then becomes a drug candidate. This entire process is referred to as lead generation. 

An interesting example of the development of a useful drug by molecular modifications of a related lead is to be found in another chemical class of antihypertensive agents epitomized by guanethidine. Maxwell et al. (21) relate the development of this drug to the observation of certain pharmacological characteristics of an earlier chemical relative, SU-4029. The preparation and properties of a variety of related compounds have been presented by Mull... 

From a practical end result, it is evident that molecular modifications of a new compound lead have yielded anywhere from little or no to moderate to distinct improvements in different instances but that, in each case, the usefulness of molecular modification was initially unpredictable. 

From the standpoint of random vs. rational approaches to molecular modifications, our present state of knowledge requires us to lean on the first before we can exploit the second. New classes of active compounds usually are discovered by random testing or by accident. The exploitation of a lead becomes more rational as more modifications are made. The retrospective correlations made possible after molecular modifications are of only limited value in rationalizing modifications in a different kind of molecule or with the same group of molecules for other biological properties. 

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