scholarly journals Rational Drug Design of Antineoplastic Agents Using 3D-QSAR, Cheminformatic, and Virtual Screening Approaches

2019 ◽  
Vol 26 (21) ◽  
pp. 3874-3889 ◽  
Author(s):  
Jelica Vucicevic ◽  
Katarina Nikolic ◽  
John B.O. Mitchell
Keyword(s):  
Virtual Screening ◽  
Drug Design ◽  
Antineoplastic Agents ◽  
Drug Targets ◽  
3D Qsar ◽  
Pharmacophore Modeling ◽  
Rational Drug Design ◽  
Bioactive Molecules ◽  
Computational Approaches ◽  
Rational Drug

Background: Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation. Results: Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery. Similarity, searches and virtual screening are used to identify molecules with an increased probability to interact with drug targets of interest, while the other computational approaches are applied for the design and evaluation of molecules with enhanced activity and improved safety profile. Conclusion: In this review are described the main in silico techniques used in rational drug design of antineoplastic agents and presented optimal combinations of computational methods for design of more efficient antineoplastic drugs.

scholarly journals NICEdrug.ch, a workflow for rational drug design and systems-level analysis of drug metabolism

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Homa MohammadiPeyhani ◽  
Anush Chiappino-Pepe ◽  
Kiandokht Haddadi ◽  
Jasmin Hafner ◽  
Noushin Hadadi ◽  
...  
Keyword(s):  
Drug Targets ◽  
Drug Repurposing ◽  
Rational Drug Design ◽  
Bioactive Molecules ◽  
Lead Discovery ◽  
Minimal Impact ◽  
Practical Applications ◽  
Rational Drug ◽  
Golden Standard ◽  
And Performance

The discovery of a drug requires over a decade of intensive research and financial investments – and still has a high risk of failure. To reduce this burden, we developed the NICEdrug.ch resource, which incorporates 250,000 bioactive molecules, and studied their enzymatic metabolic targets, fate, and toxicity. NICEdrug.ch includes a unique fingerprint that identifies reactive similarities between drug–drug and drug–metabolite pairs. We validated the application, scope, and performance of NICEdrug.ch over similar methods in the field on golden standard datasets describing drugs and metabolites sharing reactivity, drug toxicities, and drug targets. We use NICEdrug.ch to evaluate inhibition and toxicity by the anticancer drug 5-fluorouracil, and suggest avenues to alleviate its side effects. We propose shikimate 3-phosphate for targeting liver-stage malaria with minimal impact on the human host cell. Finally, NICEdrug.ch suggests over 1300 candidate drugs and food molecules to target COVID-19 and explains their inhibitory mechanism for further experimental screening. The NICEdrug.ch database is accessible online to systematically identify the reactivity of small molecules and druggable enzymes with practical applications in lead discovery and drug repurposing.

Computational and Pharmacogenomic Insights on Hypertension Treatment: Rational Drug Design and Optimization Strategies

2019 ◽  
Vol 21 (1) ◽  
pp. 18-33 ◽  
Author(s):  
Lakshmanan Loganathan ◽  
Krishnasamy Gopinath ◽  
Vadivel Murugan Sankaranarayanan ◽  
Ritushree Kukreti ◽  
Kannan Rajendran ◽  
...  
Keyword(s):  
Drug Design ◽  
Drug Targets ◽  
Antihypertensive Drugs ◽  
Rational Drug Design ◽  
Hypertension Treatment ◽  
Genetic Traits ◽  
Drug Responses ◽  
Computational Screening ◽  
Rational Drug ◽  
Multiple Drugs

Background:: Hypertension is a prevalent cardiovascular complication caused by genetic and nongenetic factors. Blood pressure (BP) management is difficult because most patients become resistant to monotherapy soon after treatment initiation. Although many antihypertensive drugs are available, some patients do not respond to multiple drugs. Identification of personalized antihypertensive treatments is a key for better BP management. Objective:: This review aimed to elucidate aspects of rational drug design and other methods to develop better hypertension management. Results:: Among hypertension-related signaling mechanisms, the renin-angiotensin-aldosterone system is the leading genetic target for hypertension treatment. Identifying a single drug that acts on multiple targets is an emerging strategy for hypertension treatment, and could be achieved by discovering new drug targets with less mutated and highly conserved regions. Extending pharmacogenomics research to include patients with hypertension receiving multiple antihypertensive drugs could help identify the genetic markers of hypertension. However, available evidence on the role of pharmacogenomics in hypertension is limited and primarily focused on candidate genes. Studies on hypertension pharmacogenomics aim to identify the genetic causes of response variations to antihypertensive drugs. Genetic association studies have identified single nucleotide polymorphisms affecting drug responses. To understand how genetic traits alter drug responses, computational screening of mutagenesis can be utilized to observe drug response variations at the protein level, which can help identify new inhibitors and drug targets to manage hypertension. Conclusions:: Rational drug design facilitates the discovery and design of potent inhibitors. However, further research and clinical validation are required before novel inhibitors can be clinically used as antihypertensive therapies.

scholarly journals Discovery of novel aminopiperidinyl amide CXCR4 modulators through virtual screening and rational drug design

2020 ◽  
Vol 201 ◽  
pp. 112479 ◽  
Author(s):  
Yoon Hyeun Oum ◽  
Steven A. Kell ◽  
Younghyoun Yoon ◽  
Zhongxing Liang ◽  
Pieter Burger ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Design ◽  
Rational Drug Design ◽  
Rational Drug

scholarly journals Virtual screening following rational drug design based approach for introducing new anti amyloid beta aggregation agent

2017 ◽  
Vol 13 (02) ◽  
pp. 42-45 ◽  
Author(s):  
Garshasb Rigi ◽  
◽  
Mohammad Vala Ashdar Nakhaei ◽  
Hoda Eidipour ◽  
Arshia Najimi ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Design ◽  
Amyloid Beta ◽  
Rational Drug Design ◽  
Rational Drug

scholarly journals Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening

2019 ◽  
Vol 20 (16) ◽  
pp. 4014 ◽  
Author(s):  
David Ramírez ◽  
Guierdy Concha ◽  
Bárbara Arévalo ◽  
Luis Prent-Peñaloza ◽  
Leandro Zúñiga ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Pharmacophore Modeling ◽  
Free Energy Calculations ◽  
Rational Drug Design ◽  
Channel Blockers ◽  
Rational Drug ◽  
Screening Protocol ◽  
Cancer Types ◽  
Design Protocol ◽  
Pore Domain

TASK-3 is a two-pore domain potassium (K2P) channel highly expressed in the hippocampus, cerebellum, and cortex. TASK-3 has been identified as an oncogenic potassium channel and it is overexpressed in different cancer types. For this reason, the development of new TASK-3 blockers could influence the pharmacological treatment of cancer and several neurological conditions. In the present work, we searched for novel TASK-3 blockers by using a virtual screening protocol that includes pharmacophore modeling, molecular docking, and free energy calculations. With this protocol, 19 potential TASK-3 blockers were identified. These molecules were tested in TASK-3 using patch clamp, and one blocker (DR16) was identified with an IC50 = 56.8 ± 3.9 μM. Using DR16 as a scaffold, we designed DR16.1, a novel TASK-3 inhibitor, with an IC50 = 14.2 ± 3.4 μM. Our finding takes on greater relevance considering that not many inhibitory TASK-3 modulators have been reported in the scientific literature until today. These two novel TASK-3 channel inhibitors (DR16 and DR16.1) are the first compounds found using a pharmacophore-based virtual screening and rational drug design protocol.

Characterization of the Trypanosoma brucei Pteridine Reductase Active- Site using Computational Docking and Virtual Screening Techniques

2020 ◽  
Vol 16 (5) ◽  
pp. 583-598 ◽  
Author(s):  
Hina Shamshad ◽  
Abdul Hafiz ◽  
Ismail I. Althagafi ◽  
Maria Saeed ◽  
Agha Zeeshan Mirza
Keyword(s):  
Virtual Screening ◽  
Drug Design ◽  
Trypanosoma Brucei ◽  
Active Site ◽  
Critical Role ◽  
Rational Drug Design ◽  
Small Scale ◽  
Chain Flexibility ◽  
Rational Drug

Background: Human African trypanosomiasis is a fatal disease prevalent in approximately 36 sub-Saharan countries. Emerging reports of drug resistance in Trypanosoma brucei are a serious cause of concern as only limited drugs are available for the treatment of the disease. Pteridine reductase is an enzyme of Trypanosoma brucei. Methods: It plays a critical role in the pterin metabolic pathway that is absolutely essential for its survival in the human host. The success of finding a potent inhibitor in structure-based drug design lies within the ability of computational tools to efficiently and accurately dock a ligand into the binding cavity of the target protein. Here we report the computational characterization of Trypanosoma brucei pteridine reductase (Tb-PR) active-site using twenty-four high-resolution co-crystal structures with various drugs. Structurally, the Tb-PR active site can be grouped in two clusters; one with high Root Mean Square Deviation (RMSD) of atomic positions and another with low RMSD of atomic positions. These clusters provide fresh insight for rational drug design against Tb-PR. Henceforth, the effect of several factors on docking accuracy, including ligand and protein flexibility were analyzed using Fred. Results: The online server was used to analyze the side chain flexibility and four proteins were selected on the basis of results. The proteins were subjected to small-scale virtual screening using 85 compounds, and statistics were calculated using Bedroc and roc curves. The enrichment factor was also calculated for the proteins and scoring functions. The best scoring function was used to understand the ligand protein interactions with top common compounds of four proteins. In addition, we made a 3D structural comparison between the active site of Tb-PR and Leishmania major pteridine reductase (Lm- PR). We described key structural differences between Tb-PR and Lm-PR that can be exploited for rational drug design against these two human parasites. Conclusion: The results indicated that relying just on re-docking and cross-docking experiments for virtual screening of libraries isn’t enough and results might be misleading. Hence it has been suggested that small scale virtual screening should be performed prior to large scale screening.

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