8 Ligand Becomes Drug!
Drug research encompasses by various pipelines to achieve common goal, i.e., new
therapeutic molecules. After the successful identification of the novel ligand or lead
molecules by either computational or medicinal chemistry approach, each molecule
must be characterized for absorption, distribution, metabolism, excretion, and
toxicity (ADME-Tox) properties along with pharmacokinetic/pharmacodynamic
(PK/PD) activity that decides the success rate of the drug [273, 274]. Evaluation of
these properties belongs to the pre-clinical stage, and result of this stage decides the
advancement of novel chemical entity (NCE) to clinical stage. Failure of the drug is
dependent on the targeted therapeutic area; comparatively drug targeted to cardiovascular has maximum chance of success than CNS targeted [261]. So, successful candidates have to fulfill the essential criteria of potency, selectivity, oral
bioavailability, therapeutic efficacy, along with an acceptable side effect profile
[275]. Testing of thousands of leads molecules, found to be active against any
disease, requires huge amount of money and time, and also it is not always easy to
perform every test [276]. Understanding from the already prescribed drugs and
knowledge from the failure rate during the different clinical stages has provided
directions and specified various properties of chemicals which can be utilized to
assess the lead molecules before performing costly and complex clinical tests [277].
Detailed information about ADME-Tox and its role in successful drug design is
reviewed and available in many recent literatures [273, 278, 279]; however, major
application of these properties is related to reduction in clinical drug failures from
40 to 10% [280]. This reduction has been seen with the advancement in the
chemoinformatics and computational application in drug development process. As
mentioned in the ligand design libraries, various physiochemical properties based
on rules have been set to develop the lead-like and drug-like libraries to screen
[281–284]. Along with these filters, for further libraries optimization filters like Pan
Assay Interference Compounds (PAINS) and ALARM-NMR have been developed
to remove known toxicophores or metabolically liable moieties which can interfere
with the assay protocol [285, 286].
9 Summary
In this review, we have summarized many methods related to structure of receptor,
characterization of active sites and subsites, binding affinity calculations, docking
with specific poses, ranking chemicals and elucidated existing challenges in these
methods. In spite of many mathematically and computationally elegant tools to
understand and perform efficiently docking and scoring for large number of compounds, the success of identifying novel inhibitor of infectious disease and challenges thereof is still significantly high. Some of the solutions are already evident
but many are yet to find. Still to ponder, how to estimate efficiently the effect of
160
S. K. Panday and I. Ghosh
Drug research encompasses by various pipelines to achieve common goal, i.e., new
therapeutic molecules. After the successful identification of the novel ligand or lead
molecules by either computational or medicinal chemistry approach, each molecule
must be characterized for absorption, distribution, metabolism, excretion, and
toxicity (ADME-Tox) properties along with pharmacokinetic/pharmacodynamic
(PK/PD) activity that decides the success rate of the drug [273, 274]. Evaluation of
these properties belongs to the pre-clinical stage, and result of this stage decides the
advancement of novel chemical entity (NCE) to clinical stage. Failure of the drug is
dependent on the targeted therapeutic area; comparatively drug targeted to cardiovascular has maximum chance of success than CNS targeted [261]. So, successful candidates have to fulfill the essential criteria of potency, selectivity, oral
bioavailability, therapeutic efficacy, along with an acceptable side effect profile
[275]. Testing of thousands of leads molecules, found to be active against any
disease, requires huge amount of money and time, and also it is not always easy to
perform every test [276]. Understanding from the already prescribed drugs and
knowledge from the failure rate during the different clinical stages has provided
directions and specified various properties of chemicals which can be utilized to
assess the lead molecules before performing costly and complex clinical tests [277].
Detailed information about ADME-Tox and its role in successful drug design is
reviewed and available in many recent literatures [273, 278, 279]; however, major
application of these properties is related to reduction in clinical drug failures from
40 to 10% [280]. This reduction has been seen with the advancement in the
chemoinformatics and computational application in drug development process. As
mentioned in the ligand design libraries, various physiochemical properties based
on rules have been set to develop the lead-like and drug-like libraries to screen
[281–284]. Along with these filters, for further libraries optimization filters like Pan
Assay Interference Compounds (PAINS) and ALARM-NMR have been developed
to remove known toxicophores or metabolically liable moieties which can interfere
with the assay protocol [285, 286].
9 Summary
In this review, we have summarized many methods related to structure of receptor,
characterization of active sites and subsites, binding affinity calculations, docking
with specific poses, ranking chemicals and elucidated existing challenges in these
methods. In spite of many mathematically and computationally elegant tools to
understand and perform efficiently docking and scoring for large number of compounds, the success of identifying novel inhibitor of infectious disease and challenges thereof is still significantly high. Some of the solutions are already evident
but many are yet to find. Still to ponder, how to estimate efficiently the effect of
160
S. K. Panday and I. Ghosh