Virtual screening, ADMET profiling, molecular docking and dynamics approaches to search for potent selective natural molecules based inhibitors against metallothionein-III to study Alzheimer's disease.
BACKGROUND
Metallothionein-III (MT-III) displays neuro-inhibitory activity and is involved in the repair of neuronal damage. An altered expression level of MT-III suggests that it could be a mitigating factor in Alzheimer's disease (AD) neuronal dysfunction. Currently there are limited marketed drugs available against MT-III. The inhibitors are mostly pseudo-peptide based with limited ADMET. In our present study, available database InterBioScreen (natural compounds) was screened out for MT-III. Pharmacodynamics and pharmacokinetic studies were performed. Molecular docking and simulations of top hit molecules were performed to study complex stability.


RESULTS
Study reveals potent selective molecules that interact and form hydrogen bonds with amino acids Ser-6 and Lys-22 are common to established melatonin inhibitors for MT-III. These include DMHMIO, MCA B and s27533 derivatives. The ADMET profiling was better with comparable interaction energy values. It includes properties like blood brain barrier, hepatotoxicity, druggability, mutagenicity and carcinogenicity. Molecular dynamics studies were performed to validate our findings.
Department of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology Technická 12, 61200 Brno, Czech Republic. Electronic address: roy@feec.vutbr.cz.
Sudeep
S
Roy
Biotechnology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India. Electronic address: akhil2687@gmail.com.
Akhil
A
Kumar
School of Biotechnology, Yeungnam University, Gyeongsan 712749, Republic of Korea. Electronic address: mohdhassanbaig@gmail.com.
Mohd Hassan
MH
Baig
Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Bld. A18, 625 00 Brno, Czech Republic. Electronic address: masarik@med.muni.cz.
Michal
M
Masařík
International Clinical Research Center - Center of Biomedical Engineering, St. Anne's University Hospital Brno and Department of Biomedical Engineering, FEEC, Brno University of Technology, Brno, Czech Republic. Electronic address: ivo.provaznik@fnusa.cz.
Ivo
I
Provazník
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D055592:Biophysical Phenomena; D006801:Humans; D000090023:Metallothionein 3; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins
ADMET; Alzheimer’s disease; Metallothionein-III; Molecular dynamics; Virtual screening