Dileep KV

References (7)

Title : Lobeline: A multifunctional alkaloid modulates cholinergic and glutamatergic activities - Remya_2023_IUBMB.Life__
Author(s) : Remya C , Dileep KV , Variyar EJ , Omkumar RV , Sadasivan C
Ref : IUBMB Life , : , 2023
Abstract : Developing drugs for Alzheimer's disease (AD) is an extremely challenging task due to its devastating pathology. Previous studies have indicated that natural compounds play a crucial role as lead molecules in the development of drugs. Even though, there are remarkable technological advancements in the isolation and synthesis of natural compounds, the targets for many of them are still unknown. In the present study, lobeline, a piperidine alkaloid has been identified as a cholinesterase inhibitor through chemical similarity assisted target fishing method. The structural similarities between lobeline and donepezil, a known acetylcholinesterase (AChE) inhibitor encouraged us to hypothesize that lobeline may also exhibit AChE inhibitory properties. It was further confirmed by in silico, in vitro and biophysical studies that lobeline could inhibit cholinesterase. The binding profiles indicated that lobeline has a higher affinity for AChE than BChE. Since excitotoxicity is one of the major pathological events associated with AD progression, we also investigated the neuroprotective potential of lobeline against glutamate mediated excitotoxicity in rat primary cortical neurons. The cell based NMDA receptor (NMDAR) assay with lobeline suggested that neuroprotective potential of lobeline is mediated through the blockade of NMDAR activity.
ESTHER : Remya_2023_IUBMB.Life__
PubMedSearch : Remya_2023_IUBMB.Life__
PubMedID: 37335270

Title : Sub-pocket-focused designing of tacrine derivatives as potential acetylcholinesterase inhibitors - Babu_2023_Comput.Biol.Med_155_106666
Author(s) : Babu A , John M , Liji MJ , Maria E , Bhaskar SJ , Binukmar BK , Sajith AM , Reddy EK , Dileep KV , Sunil K
Ref : Computers in Biology & Medicine , 155 :106666 , 2023
Abstract : Human acetylcholinesterase (hAChE) has a potential role in the management of acetylcholine, one of the neurotransmitters that modulate the overall activity of cholinergic system, AChE inhibitors have a greater impact in the therapeutics. Though the atomic structure of hAChE has been extensively studied, the precise active site geometry upon binding to different ligands are yet to be explored. In the present study, an extensive structural analysis of our recently reported hAChE-tacrine complex has carried out and revealed the presence of two prominent sub-pockets located at the vicinity of the hAChE active site. Structural bioinformatics assisted studies designed 132 putative sub-pockets focused tacrine derivatives (SPFTDs), their molecular docking, free energy estimations revealed that they are stronger than tacrine in terms of binding affinity. Our in vitro studies also supported the in silico findings, all these SPFTDs are having better potencies than tacrine. Cytotoxic nature of these SPFTDs on HepG2 and Neuro-2a cell lines, diminishes the possibilities for future in vivo studies. However, the identification of these sub pockets and the SPFTDs paved a new way to the future drug discovery especially since AChE is one of the promising and approved drug targets in treatment of AD drug discovery.
ESTHER : Babu_2023_Comput.Biol.Med_155_106666
PubMedSearch : Babu_2023_Comput.Biol.Med_155_106666
PubMedID: 36841058

Title : Crystal structure of human acetylcholinesterase in complex with tacrine: Implications for drug discovery - Dileep_2022_Int.J.Biol.Macromol_210_172
Author(s) : Dileep KV , Ihara K , Mishima-Tsumagari C , Kukimoto-Niino M , Yonemochi M , Hanada K , Shirouzu M , Zhang KYJ
Ref : Int J Biol Macromol , 210 :172 , 2022
Abstract : Alzheimer's disease (AD) is one of the most common, progressive neurodegenerative disorders affecting the aged populations. Though various disease pathologies have been suggested for AD, the impairment of the cholinergic system is one of the critical factors for the disease progression. Restoration of the cholinergic transmission through acetylcholinesterase (AChE) inhibitors is a promising disease modifying therapy. Being the first marketed drug for AD, tacrine reversibly inhibits AChE and thereby slows the breakdown of the chemical messenger acetylcholine (ACh) in the brain. However, the atomic level of interactions of tacrine towards human AChE (hAChE) is unknown for years. Hence, in the current study, we report the X-ray structure of hAChE-tacrine complex at 2.85 A resolution. The conformational heterogeneity of tacrine within the electron density was addressed with the help of molecular mechanics assisted methods and the low-energy ligand configuration is reported, which provides a mechanistic explanation for the high binding affinity of tacrine towards AChE. Additionally, structural comparison of reported hAChE structures sheds light on the conformational selection and induced fit effects of various active site residues upon binding to different ligands and provides insight for future drug design campaigns against AD where AChE is a drug target.
ESTHER : Dileep_2022_Int.J.Biol.Macromol_210_172
PubMedSearch : Dileep_2022_Int.J.Biol.Macromol_210_172
PubMedID: 35526766
Gene_locus related to this paper: human-ACHE

Title : Chemical similarity assisted search for acetylcholinesterase inhibitors: Molecular modeling and evaluation of their neuroprotective properties - Remya_2021_Int.J.Biol.Macromol__
Author(s) : Remya C , Dileep KV , Variyar EJ , Zhang KYJ , Omkumar RV , Sadasivan C
Ref : Int J Biol Macromol , : , 2021
Abstract : Alzheimer's disease (AD) is an obstinate and progressive neurodegenerative disorder, mainly characterized by cognitive decline. Increasing number of AD patients and the lack of promising treatment strategies demands novel therapeutic agents to combat various disease pathologies in AD. Recent progresses in understanding molecular mechanisms in AD helped researchers to streamline the various therapeutic approaches. Inhibiting acetylcholinesterase (AChE) activity has emerged as one of the potential treatment strategies. The present study discusses the identification of two potent AChE inhibitors (ZINC11709541 and ZINC11996936) from ZINC database through conventional in silico approaches and their in vitro validations. These inhibitors have strong preferences towards AChE than butyrylcholinesterase (BChE) and didn't evoke any significant reduction in the cell viability of HEK-293 cells and primary cortical neurons. Furthermore, promising neuroprotective properties has also been displayed against glutamate induced excitotoxicity in primary cortical neurons. The present study proposes two potential drug lead compounds for the treatment of AD, that can be used for further studies and preclinical evaluation.
ESTHER : Remya_2021_Int.J.Biol.Macromol__
PubMedSearch : Remya_2021_Int.J.Biol.Macromol__
PubMedID: 33497692

Title : Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase - Design, synthesis and biological evaluation - Remya_2021_Comput.Struct.Biotechnol.J_19_4517
Author(s) : Remya C , Dileep KV , Koti Reddy E , Mantosh K , Lakshmi K , Sarah Jacob R , Sajith AM , Jayadevi Variyar E , Anwar S , Zhang KYJ , Sadasivan C , Omkumar RV
Ref : Comput Struct Biotechnol J , 19 :4517 , 2021
Abstract : The complex and multifactorial nature of neuropsychiatric diseases demands multi-target drugs that can intervene with various sub-pathologies underlying disease progression. Targeting the impairments in cholinergic and glutamatergic neurotransmissions with small molecules has been suggested as one of the potential disease-modifying approaches for Alzheimer's disease (AD). Tacrine, a potent inhibitor of acetylcholinesterase (AChE) is the first FDA approved drug for the treatment of AD. Tacrine is also a low affinity antagonist of N-methyl-D-aspartate receptor (NMDAR). However, tacrine was withdrawn from its clinical use later due to its hepatotoxicity. With an aim to develop novel high affinity multi-target directed ligands (MTDLs) against AChE and NMDAR, with reduced hepatotoxicity, we performed in silico structure-based modifications on tacrine, chemical synthesis of the derivatives and in vitro validation of their activities. Nineteen such derivatives showed inhibition with IC(50) values in the range of 18.53 +/- 2.09 - 184.09 +/- 19.23 nM against AChE and 0.27 +/- 0.05 - 38.84 +/- 9.64 microM against NMDAR. Some of the selected compounds also protected rat primary cortical neurons from glutamate induced excitotoxicity. Two of the tacrine derived MTDLs, 201 and 208 exhibited in vivo efficacy in rats by protecting against behavioral impairment induced by administration of the excitotoxic agent, monosodium glutamate. Additionally, several of these synthesized compounds also exhibited promising inhibitory activitiy against butyrylcholinesterase. MTDL-201 was also devoid of hepatotoxicity in vivo. Given the therapeutic potential of MTDLs in disease-modifying therapy, our studies revealed several promising MTDLs among which 201 appears to be a potential candidate for immediate preclinical evaluations.
ESTHER : Remya_2021_Comput.Struct.Biotechnol.J_19_4517
PubMedSearch : Remya_2021_Comput.Struct.Biotechnol.J_19_4517
PubMedID: 34471497

Title : Flavanone glycosides as acetylcholinesterase inhibitors: computational and experimental evidence - Remya_2014_Indian.J.Pharm.Sci_76_567
Author(s) : Remya C , Dileep KV , Tintu I , Variyar EJ , Sadasivan C
Ref : Indian J Pharm Sci , 76 :567 , 2014
Abstract : Acetylcholinesterase hydrolyzes the neurotransmitter called acetylcholine and is crucially involved in the regulation of neurotransmission. One of the observable facts in the neurodegenerative disorders like Alzheimer's disease is the decrease in the level of acetylcholine. Available drugs that are used for the treatment of Alzheimer's disease are primarily acetylcholinesterase inhibitors with multiple activities. They maintain the level of acetylcholine in the brain by inhibiting the acetylcholinesterase function. Hence acetylcholinesterase inhibitors can be used as lead compounds for the development of drugs against AD. In the present study, the binding potential of four flavanone glycosides such as naringin, hesperidin, poncirin and sakuranin against acetylcholinesterase was analysed by using the method of molecular modeling and docking. The activity of the top scored compound, naringin was further investigated by enzyme inhibition studies and its inhibitory concentration (IC50) towards acetylcholinesterase was also determined.
ESTHER : Remya_2014_Indian.J.Pharm.Sci_76_567
PubMedSearch : Remya_2014_Indian.J.Pharm.Sci_76_567
PubMedID: 25593395

Title : In vitro inhibitory profile of NDGA against AChE and its in silico structural modifications based on ADME profile - Remya_2013_J.Mol.Model_19_1179
Author(s) : Remya C , Dileep KV , Tintu I , Variyar EJ , Sadasivan C
Ref : J Mol Model , 19 :1179 , 2013
Abstract : Acetylcholinesterase (AChE) inhibitors are currently in focus for the pharmacotherapy of Alzheimer's disease (AD). These inhibitors increase the level of acetylcholine in the brain and facilitate cholinergic neurotransmission. AChE inhibitors such as rivastigmine, galantamine, physostigmine and huperzine are obtained from plants, indicating that plants can serve as a potential source for novel AChE inhibitors. We have performed a virtual screening of diverse natural products with distinct chemical structure against AChE. NDGA was one among the top scored compounds and was selected for enzyme kinetic studies. The IC(50) of NDGA on AChE was 46.2 muM. However, NDGA showed very poor central nervous system (CNS) activity and blood-brain barrier (BBB) penetration. In silico structural modification on NDGA was carried out in order to obtain derivatives with better CNS activity as well as BBB penetration. The studies revealed that some of the designed compounds can be used as lead molecules for the development of drugs against AD.
ESTHER : Remya_2013_J.Mol.Model_19_1179
PubMedSearch : Remya_2013_J.Mol.Model_19_1179
PubMedID: 23229229