Systems Pharmacology
Table 2: Select examples of FDA-approved commercially-available systems pharmacology drugs DISEASE INDICATION
CNS-Neurological Schizophrenia, Adjuvent-
Parkinson’s Disease Bipolar Mania
Acute Mania
Oncology Thyroid Cancer
Breast Cancer- Her2(+) Breast Cancer AML- FLT3(+)
Cardiovascular Cardiac Arrhythmia
Infection Hepatitis B, Adjuvent-HIV
SYSTEMS PHARMACOLOGY DRUG Brexpiprazole (Rexulti)
Safinamde (Xadago) Cariprazine (Vraylar)
Asenapine (Saphris) D2, 3 : 5H-T1A, 2A, 2B, 7 : Alpha1A, 1B, 1D, 2C MAO-B, Dopamine-RI, Blocks Na+/Ca2+ Channels D2C, 2S, 3, 5H-T1A, 2A, 2B, 2C, 7 :Alpha1A : H1 : mACh D1-4 : 5H-T1A, 1B, 2A-C, 5A, 6, 7 : Alpha 2A-C : H1,2 35
35 35
34 MULTI-TARGETS REFS
Lenvatinib (Lenvima) Neratinib (Nerlynx) Ribociclib (Kisqall) Midostaurin (Rydapt)
VEGFR1, 2, 3 Kinases Her2, EGFR Kinases
Cyclin D1 : CDK4, 6 FLT3-mut : c-kit : PDGFR : src : VEGFR
35 35 35 35
Dronedarone (Mutaq)
Na+ & K+, L-type Ca2+ channels
37
Tenofovir (Viread)
Viral Reverse Transcriptase, DNA and Mitochondrial DNA Polymerase
38
Implementation of systems pharmacology Talevi has discussed systems pharmacology drugs in the context of the substrate-enzyme ‘lock and key’ model. He has suggested that a multi-target drug could be conceived as a “skeleton or master key capable of [simultaneously] unlocking several locks”. However, he opined subsequently that such a model was simplistic and did not adequately describe the effect of a drug on multi-targets over a prolonged period of time due to significant up-and- down regulation of gene signatures34. A detailed comparative systems analysis (ie the systems response profile consisting of healthy versus patho- biological versus drug effect systems biology anal- yses) is required to produce systems pharmacologic drugs23, but how to efficiently go about both ratio- nale target selection and drug candidate design in such a complex system? Recently, Ramsey and col- leagues discussed these issues and made the follow- ing salient points presented below35:
i) Target selection: It is necessary to have a compre- 40
hensive understanding of target-disease associa- tions, pathway-target-drug-disease relationships, as well as adverse events profiling capability. In addition it should be understood that target selec- tion is either additive (targets on the same path- way) or synergistic (targets on functionally com- plementary pathways) in nature.
ii) Drug candidate design/selection: The typical approach is to integrate a different combination of pharmacophores (a molecular recognition feature of a substrate/ligand necessary to bind to a biolog- ical macromolecule such as a target protein) into the systems pharmacology drug candidate. The design of the candidate drug is typically defined by the nature of the targets, the availability of starting frameworks and the chemical tractability. Beyond that, the essential requirement of multi-target com- pounds is that each pharmacophore retains the ability to interact with its specific target. These challenging tasks involve consideration of structure-activity relationships that determine
Drug Discovery World Winter 2018/19
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