The identification of such cellular targets for drug design necessitates an appreciation
of the anatomy of cellular structure. These endogenous macromolecules are the catalysts
and molecular machinery that enable the cell to perform its normal metabolic functions;
accordingly, they afford numerous druggable targets. Finally, if that approach is not
sufficient, it would next be necessary to attack the agent causing the disease process,
perhaps a bacterium or virus.
MANMETS thus provides a sequential step-by-step working algorithm with which
to design a drug for a particular disease state:
- Design the drug to manipulate endogenous messengers that would normally respond
to the disease process. - Design the drug to influence endogenous targets involved in the disease but not
influenced by messenger systems. - Design the drug to attack exogenous causes of the disease.
For example, when confronted with the task of designing drugs for systemic arterial
hypertension and atherosclerosis, there are many targets. Following Step 1, drugs could
be designed to interact with messenger neurotransmitter (adrenergic) receptors (e.g.,
“beta-blockers”) or messenger hormonal (renin–angiotensin) receptors to lower blood
pressure. Following Step 2, drugs could be designed to interact with non-messenger pro-
tein targets such as enzymes involved in fluid homeostasis (e.g., diuretics targeting the
carbonic anhydrase enzyme). Following Step 3, drugs could be designed to interact with
exogenous targets (e.g., chlamydia infection) that some workers hypothesize are involved
with augmenting the arterial wall damage initiated by high blood pressure.
The MANMETS system also facilitates logical methods for remembering the side
effects of drugs, without having to resort to “brute memorization.” For example, drugs
used for the treatment of psychosis may cause the movement disorder known as parkin-
sonism as a side effect because of their interactions with dopamine receptors. Similarly,
drugs used for the treatment of epilepsy may produce untoward events in individuals
susceptible to heart arrhythmias because seizures and cardiac arrhythmias are both
mediated by voltage-gated ion channels.
A final advantage of MANMETS is that it is not merely a catalogue of information
pertinent to drug design and medicinal chemistry. It provides a structural andconcep-
tual framework that enables this knowledge and information to be stored and logically
manipulated in a meaningful way for purposes of practical drug design. As an infor-
mation storage, processing, and utilization framework, MANMETS endeavors to pro-
vide a conceptual outline that logically interfaces the practice of medicinal chemistry
with bioinformatics and cheminformatics. MANMETS is a molecular-level system that
provides a comprehensive organization of druggable targets—past, present and future;
future targets emerging from genomics/proteomics research can be readily integrated
into the MANMETS system.
BIOCHEMICAL CONSIDERATIONS IN DRUG DESIGN 191