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Computational design and evaluation employed DFT, molecular docking, molecular
dynamics, and ADMET analysis of salen-based drug candidates for potential cancer
and tuberculosis treatment
#MMPMID41384082
Hossain K
; Akter J
; Islam MH
; Fabiha T
; Hasan MM
; Afreen N
; Uzzaman M
In Silico Pharmacol
2026[]; 14
(1
): 3
PMID41384082
show ga
Salen (SL) ligands are known for their tetradentate N(2)O(2) coordination,
planar, and rigid structure. It attracts significant interest due to its diverse
biological activities. However, challenges like cytotoxicity, low solubility, and
physiological instability hinder the therapeutic applications. To overcome these
challenges, an in-silico approach has been utilized to design SL-based compounds
with functional group modifications and evaluate them to enhance their anticancer
and antituberculosis activities. The B3LYP functional and 6-31?+?G (d, p) basis
set were used to optimize the modified structures. Most of the derivatives,
especially SL5 ( -?1295.03 Hartree), SL6 ( -?1327.15 Hartree), and SL7 (
-?1703.61 Hartree), showed better thermodynamic stability than the parent (
-?879.06 Hartree), and higher dipole moments ranging from 3.65 to 6.68 than the
parent (1.25) in Debye. The energy gap between the highest occupied molecular
orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) was lower,
indicating these compounds have higher chemical reactivity. Docking results
revealed stronger binding affinities for SL5 ( -?8.9 kcal/mol), SL6 (
-?8.9 kcal/mol), and SL7 ( -?9.3 kcal/mol) derivatives. Hydrogen bonds,
carbon-hydrogen bonds, alkyl, and ?-alabsorptionkyl are the crucial non-bonding
interactions. Further, molecular dynamics (MD) simulations were done to
investigate the stability and interaction of drugs and proteins. The RMSD value
of Mean?±?SD for SL6 is 1.21?±?0.13 and for SL5 is 1.48?±?0.26, as the most
promising drug within 3ZHH and 1MQ4 protein, respectively. ADMET predicts better
pharmacokinetic properties, such as high human intestinal absorption (HIA) values
for SL5 (0.97), SL6 (0.96), and SL7 (0.99), and minimum blood-brain barrier (BBB)
penetration, such as SL5 (0.21), SL6 (0.07). Additionally, gastrointestinal
bleeding, atrial fibrillation, and allergic dermatitis adverse effects have been
reduced in the most promising drugs than the parent. This computational study
proves that these drug candidates can be utilized as medicines, as they exhibit
higher stability and safety with enhanced drug-like properties. SUPPLEMENTARY
INFORMATION: The online version contains supplementary material available at
10.1007/s40203-025-00500-8.
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