Computer Aided Drug Design and its Application to the Development of Potential Drugs for Neurodegenerative Disorders

Baig, Mohammad Hassan; Ahmad, Khurshid; Rabbani, Gulam; Danishuddin, Mohd

doi:10.2174/1570159x15666171016163510

Cited by 144 publications

(65 citation statements)

References 93 publications

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“…An in-depth understanding of biological processes is still often hampered by a lack of detailed knowledge of protein structures [ 18 ]. The determination of the structure of the target protein is a prerequisite for CADD [ 19 ]. Structural elucidation of the target protein can be performed by experimental tools including, but not limited to, nuclear magnetic resonance (NMR) spectroscopy, Cryo-EM, and X-ray crystallography [ 20 , 21 ].…”

Section: Computer-aided Drug Designmentioning

confidence: 99%

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

Salman

Al-Obaidi

Kitchen

et al. 2021

IJMS

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Neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.

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Section: Computer-aided Drug Designmentioning

confidence: 99%

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

Salman

Al-Obaidi

Kitchen

et al. 2021

IJMS

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show abstract

“…CADD may overcome the disadvantages of traditional drug development processes, including their long clinical trial cycle period, low combinatorial variety and low efficiency, by simulating the interaction between drugs and receptors of biological macromolecules ( 11 , 12 ). CADD has identified numerous drugs to date, and is becoming a core technology in the field of novel drug development ( 13 ). In particular, it may aid to identify more optimized TMZ derivatives with enhanced therapeutic effect in glioma patients.…”

Section: Introductionmentioning

confidence: 99%

Computer‑aided design of temozolomide derivatives based on alkylglycerone phosphate synthase structure with isothiocyanate and their pharmacokinetic/toxicity prediction and anti‑tumor activity in vitro

Yang

et al. 2018

biom rep

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Despite the development of temozolomide (TMZ), a novel type of glioma therapeutic drug, malignant glioma remains to cause severe damage to human health. The present study aimed to utilize the molecular biological differences between tumor and normal cells to design TMZ derivatives with improved selectivity and targeting using computer-aided drug design (CADD). Taking alkylglycerone phosphate synthase (AGPS) as a target, a 3D structure-activity relationship model was built using CADD technology; molecular docking of isothiocyanate (ITC) and TMZ compounds was conducted; ITC-TMZ derivatives were designed; and predictions on the absorption, distribution, metabolism and excretion (ADME) processes and toxicity of the ITC-TMZ derivatives were established in order to obtain improved understanding of the structure-activity relationship of the candidate compounds. Using these techniques, it was identified that the docking scores of the structural derivatives S1-9 were higher than that of TMZ. Additionally, S3, −6, −7, −8, −9 and −10 exhibited enhanced ADME and similar toxicity to that of TMZ. The half maximal inhibitory concentrations of the CADD derivatives were also assessed in the glioma U87MG and U251 cell lines, and the activities of S1, −3, −8 and −10 were determined to be greater than that of TMZ, suggesting their potential as anti-cancer drugs with adequate AGPS targeting, ADME/toxicity and anti-tumor activity.

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“…This aim will be achieved by designing a series of new analogs and evaluate their antiproliferative activities. The design of the new analogs will use different techniques of computer-aided drug design [ 21 , 22 , 23 ], which proved successful in optimization of lead compounds, will be used to in the optimization of compound 10 .…”

Section: Introductionmentioning

confidence: 99%

In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

et al. 2021

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In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed based on compound 10, and a pharmacophore search was performed. Structural analysis of the top scoring hits and a docking study were used to select the best derivatives for the synthesis. Chemical synthesis and structural elucidation of compounds 16a–h were discussed. The antiproliferative activity of 16a–h was evaluated against three cancer (MCF7, A2780 and HT29, IC50 = 0.01–40.50 μM) and one normal MRC5 (IC50 = 1.27–24.06 μM) cell lines using the MTT assay. The results revealed the highest antiproliferative activity against MCF7 cells for 16g (IC50 = 0.01 μM) with an exceptionally high selectivity index of (SI = 578). Cell cycle analysis of MCF7 cells treated with compound 16g revealed a cell cycle arrest at the G2/M phase. In addition, compound 16g induced a dose-dependent increase in apoptotic events in MCF7 cells compared to the control. In silico target prediction of compound 16g showed six potential targets that could mediate these activities. Molecular docking analysis of compound 16g revealed high binding affinities toward COX-2, MAP P38α, EGFR, and CDK2. The results of the MD simulation revealed low RMSD values and high negative binding free energies for the two complexes formed between compound 16g with EGFR, and CDK2, while COX-2 was in the third order. These results highlighted a great potentiality for 16g to inhibit both CDK2 and EGFR. Taken together, the results mentioned above highlighted compound 16g as a potential anticancer agent.

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Computer Aided Drug Design and its Application to the Development of Potential Drugs for Neurodegenerative Disorders

Abstract: CADD can assist researchers studying interactions between drugs and receptors. We believe this review will be helpful for better understanding of CADD and its applications towards the discovery of new drug candidates against various fatal NDs.

Cited by 144 publications

References 93 publications

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

Computer‑aided design of temozolomide derivatives based on alkylglycerone phosphate synthase structure with isothiocyanate and their pharmacokinetic/toxicity prediction and anti‑tumor activity in vitro

In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

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