Computational chemistry in drug lead discovery and design

Cavasotto, Claudio N.; Aucar, María Gabriela; Adler, Natalia S.

doi:10.1002/qua.25678

Cited by 61 publications

(47 citation statements)

References 209 publications

(309 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Computer-aided drug design is often used to explore the probable inhibitor, resulting in a reduction of cost and time for therapeutic growth 23 . During the issue, the ligand-binding affinity is normally required to be calculated 24 since a more efficient ligand often adopts a stronger binding affinity 25 . Numerous approaches were developed in order to resolve the problem 26 – 29 .…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, structure, in vitro cytotoxic activity evaluation and docking studies on target enzyme GSK-3β of new indirubin-3ʹ-oxime derivatives

Dan

Quang

Truong

et al. 2020

Sci Rep

View full text Add to dashboard Cite

The addition of chalcone and amine components into indirubin-3′-oxime resulted in 15 new derivatives with high yields. Structures of new derivatives were also elucidated through 1D, 2D-NMR and HR-MS(eSi) spectra and X-ray crystallography. All designed compounds were screened for cytotoxic activity against four human cancer cell lines (HepG2, LU-1, SW480 and HL-60) and one human normal kidney cell line (HEK-293). Compound 6f exhibited the most marked cytotoxicity meanwhile cytotoxicity of compounds 6e, 6h and 6l was more profound toward cancer cell lines than toward normal cell. These new derivatives were further analyzed via molecular docking studies on GSK-3β enzyme. Docking analysis shows that most of the derivatives exhibited potential inhibition activity against GSK-3β with characteristic interacting residues in the binding site. The fast pulling of ligand scheme was then employed to refine the binding affinity and mechanism between ligands and GSK-3β enzyme. the computational results are expected to contribute to predicting enzyme target of the trial inhibitors and their possible interaction, from which the design of new cytotoxic agents could be created in the future. Cancer is ranked second globally as cause of death. The disease originated due to the inability of cells to control growth, often leading to the formation of cancerous tumors or liquid cancer. (i.e. leukemia and lymphoma cancer). Routines for cancer treatment consist of chemotherapy and radiotherapy where the former utilizes molecule-size drugs aiming at eradication and inhibition of cancer tumors. However, this treatment technique has been shown to suffer from several inherent shortcomings including the development of drug resistance, off-target toxicity and limited targeting capabilities 1,2. Glycogen synthase kinase-3 (GSK-3) is defined as a multifunctional serine/threonine protein kinase that regulates the phosphorylation of various cellular targets 3. The function of GSK-3 is essential for the development

show abstract

Section: Resultsmentioning

confidence: 99%

Design, synthesis, structure, in vitro cytotoxic activity evaluation and docking studies on target enzyme GSK-3β of new indirubin-3ʹ-oxime derivatives

Dan

Quang

Truong

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…In theoretical chemistry field, the fundamental approach of developing, design and utilizing molecular derivatives from 2D descriptors, 3D descriptors, and 3D-QSAR concept is a substantial base rule in the lead molecules discovery and lead scaffold hopping field 8 . In practical, the goal of this approach is the attempt to model and discover novel molecules by replacement of selected chemical groups to generate new bioisosterism with better pharmacological therapeutic potency can be used as promising active drugs 9 . These approaches include many applications includes pharmacophore similarity search, molecular virtual screening, de novo model design, and topology similarity search.…”

Section: Introductionmentioning

confidence: 99%

Molecular drug design and docking study of novel n- substituted celecoxib derivatives as selective cyclooxygenase-2 inhibitors

Ezzat¹,

Razik²

2020

actapharm

View full text Add to dashboard Cite

Celecoxib is one of the best potent nonsteroidal anti-inflammatory drug (NSAID) used as cyclooxygenase-2 (COX-2) selective inhibitor. For decades it effectively used in pain and inflammation treatment because the ability of reducing prostaglandin (PG) synthesis by obstruct the transformation of arachidonic acid to PGH2. But several serious side effects synchronized includes kidney failure, nausea, gastrointestinal tract bleeding, myocardial infarction, abdominal pain, and finally diarrhea. In this paper, a total of 155 Celecoxib derivatives were successfully docked inside crystal structure of cyclooxygenase-2 (COX-2) enzyme to estimate the potency of each derivative to bind inside active site. The highest twenty effective derivatives were recorded with docking score range of (-16.997 to-14.611) kcal/mol.

show abstract

“…Most docking developments have been mainly rooted in molecular mechanics (MM) force-fields (FF). However, to better characterize protein-ligand interactions, at least in some cases, the use of a quantum mechanical (QM) description would be necessary (Cavasotto et al, 2019). The QM formulation is theoretically exact, as in principle, it accounts for all contributions to the energy (including terms or effects usually missing in FFs, such as electronic polarization, charge transfer, halogen bonding, and covalent-bond formation).…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Docking Using Quantum Mechanical Scoring

Cavasotto

Aucar

2020

Front. Chem.

Self Cite

View full text Add to dashboard Cite

Today high-throughput docking is one of the most commonly used computational tools in drug lead discovery. While there has been an impressive methodological improvement in docking accuracy, docking scoring still remains an open challenge. Most docking programs are rooted in classical molecular mechanics. However, to better characterize protein-ligand interactions, the use of a more accurate quantum mechanical (QM) description would be necessary. In this work, we introduce a QMbased docking scoring function for high-throughput docking and evaluate it on 10 protein systems belonging to diverse protein families, and with different binding site characteristics. Outstanding results were obtained, with our QM scoring function displaying much higher enrichment (screening power) than a traditional docking method. It is acknowledged that developments in quantum mechanics theory, algorithms and computer hardware throughout the upcoming years will allow semi-empirical (or low-cost) quantum mechanical methods to slowly replace force-field calculations. It is thus urgently needed to develop and validate novel quantum mechanical-based scoring functions for high-throughput docking toward more accurate methods for the identification and optimization of modulators of pharmaceutically relevant targets.

show abstract

Computational chemistry in drug lead discovery and design

Cited by 61 publications

References 209 publications

Design, synthesis, structure, in vitro cytotoxic activity evaluation and docking studies on target enzyme GSK-3β of new indirubin-3ʹ-oxime derivatives

Design, synthesis, structure, in vitro cytotoxic activity evaluation and docking studies on target enzyme GSK-3β of new indirubin-3ʹ-oxime derivatives

Molecular drug design and docking study of novel n- substituted celecoxib derivatives as selective cyclooxygenase-2 inhibitors

High-Throughput Docking Using Quantum Mechanical Scoring

Contact Info

Product

Resources

About