In-silico Design, ADMET Screening, Prime MM-GBSA Binding Free Energy Calculation and MD Simulation of Some Novel Phenothiazines as
5HT6R Antagonists Targeting Alzheimer’s Disease
Authors: V PREMA , A Meena , N Ramalakshmi 
Published: January 2024

Background:
Alzheimer's disease is a type of dementia that affects neuronal
function, leading to a decline in cognitive functions. Serotonin-6 (5HT6) receptors are
implicated in the etiology of neurological diseases. 5HT6 receptor antagonists act as
anti-dementia agents. PDB ID: 7YS6 represents a membrane protein, and amplification and
overexpression of this protein are associated with Alzheimer's disease. Coumarin-fused phenothiazines
are significant anti-Alzheimer's agents due to their inhibitory activity on the Serotonin-
6 receptor.

background:
Alzheimer’s disease is a type of dementia, affecting neuronal function and leading to decline in cognitive functions. Serotonin-6 (5HT6) receptors are responsible for the etiology of neurological diseases. The 5HT6 receptor antagonists are acting as anti-dementia agents. PDB id: 7YS6 is a membrane protein. Amplification and over expression of this protein is connected to Alzheimer’s disease. Coumarin fused phenothiazines are consequential anti-Alzheimer’s agents because of their Serotonin-6 receptor inhibitory activity.

Objectives:
Numerous previously unreported Coumarin-substituted Phenothiazines [A2 to A50]
were designed using in-silico methods to evaluate their 5HT6 receptor antagonistic activity. Molecular
modeling techniques were employed to study the ligands [A2 to A50] in interaction with
the Serotonin-6 receptor (PDB ID: 7YS6) using Schrödinger Suite 2019-4.

Methods:
Molecular modeling studies of the designed ligands [A2 to A50] were conducted using
the Glide module. In-silico ADMET screening was performed using the QikProp module,
and binding free energy calculations were carried out using the Prime MM-GBSA module within
the Schrödinger Suite. The binding affinity of the designed ligands [A2 to A50] towards
5HT6 receptors was determined based on Glide scores. Subsequently, ligand A31 underwent a
100 ns molecular dynamics simulation using the Desmond module of Schrödinger Suite 2020-1,
which is based in New York, NY.

Results:
The majority of the designed ligands exhibited strong hydrogen bonding interactions
and hydrophobic associations with the serotonin-6 receptor, which hinder its activity. These ligands
achieved remarkable Glide scores within the range of -4.2859 to -7.7128, in comparison to
reference standards such as Idalopirdine (-7.78149), Intepirdine (-5.20103), Latrepirdine
(-5.54853), and the co-crystallized ligand (-7.02889). In-silico ADMET properties for these
ligands fell within the recommended values for drug-likeness. It is worth noting that the
MM-GBSA binding free energy of the most potent inhibitor was positive, indicating a
strong binding interaction. Additionally, the dynamic behavior of the protein (7YS6)-ligand
(A31) complex was studied by subjecting ligand A31 to a 100 ns molecular dynamics simulation.

result:
Majority of the designed ligands had proclaimed good hydrogen bonding interconnection and hydrophobic associations to hamper serotonin-6. The ligands got remarkable glide scores in the range of -4.2859 to -7.7128 by comparing with the standards Idalopirdine (-7.78149), Intepirdine (-5.20103), Latrepirdine (-5.54853) and Co-crystallized ligand (-7.02889). The in-silico ADMET properties were within the recommended values for drug-likeness. MM-GBSA binding free energy of the most intense inhibitor is positive. The dynamic behaviour of the protein (7YS6)-ligand (A31) complex was studied by subjecting the ligand A31 to molecular dynamics simulation at 100 ns.

Conclusion:
The results of this study reveal strong evidence supporting the potential of coumarin-
substituted phenothiazine derivatives as effective Serotonin-6 receptor antagonists. Ligands
[A2 to A50], which exhibited noteworthy Glide scores, hold promise for significant anti-
Alzheimer activity. Further in-vitro and in-vivo investigations are warranted to explore and confirm
their therapeutic potential.