posted on 2021-09-01, 13:42authored bySunil Kumar, Aathira Sujathan Nair, Vaishnav Bhashkar, Sachithra Thazhathuveedu Sudevan, Vishal Payyalot Koyiparambath, Ahmed Khames, Mohamed A. Abdelgawad, Bijo Mathew
The monoamine oxidase (MAO) enzyme class is a prevalent target
for many neurodegenerative and depressive disorders. Even though scrutinization
of many promising drugs for the treatment of MAO inhibition has been
carried out in recent times, a conclusive structural requirement for
potent activity needs to be developed. Numerous approaches have been
examined for the identification of structural features for potent
MAO inhibitors (MAOIs) that mainly involve an array of computational
studies, synthetic approaches, and biological evaluation. In this
paper, we have analyzed ∼2200 well-known MAOIs to expand perceptions
in the chemical space of MAOIs. The physicochemical properties of
the MAOIs disclosed a discernible hydrophobic feature making a bunch
discrete from the central nervous system (CNS) acting drugs, as exposed
using the principal component analysis (PCA). The Murcko scaffold
structure study revealed unfavorable and favorable scaffold structures,
in both data sets, with the highest biological activity shown by the
3-phenyl-2H-chromen-2-one scaffold. This scaffold
showed a polypharmacological effect. R-group disintegration and automatic
structure–activity relationship (SAR) study resulted in identification
of substructures responsible for the inhibitory bioactivity of the
MAO-A and MAO-B enzymes. Moreover, with activity cliff analysis, significant
biological activity was detected by simple molecular conversion in
the chemical compound structure. In addition, we used the machine
learning tool to generate a hypothesis wherein pyrazole, benzene ring,
and amide containing structural functionalities can exhibit potential
biological activities. This hypothesis revealed that CNS target drugs,
C4155, C13390, C21265, C43862, C31524, C24810, C37100, C42075, and
C43644, could be repurposed as valuable candidates for the MAO-B enzyme.
For researchers, this study will bring new perceptions in the discovery
and development of MAOIs and direct lead and hit optimization for
the progress of small molecules beneficial for MAO-targeting associated
diseases.