Molecular modeling in drug discovery

Adelusi, Temitope Isaac; Oyedele, Abdul-Quddus Kehinde; Boyenle, Ibrahim Damilare; Ogunlana, Abdeen Tunde; Adeyemi, Rofiat; Ukachi, Chiamaka Divine; Idris, Mukhtar Oluwaseun; Olaoba, Olamide Tosin; Adedotun, Ibrahim Olaide; Kolawole, Oladipo Elijah; Yin, Xiaoxing; Abdul-Hammed, Misbaudeen

doi:10.1016/j.imu.2022.100880

Cited by 163 publications

(80 citation statements)

References 216 publications

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“…We used molecular docking [ 46 ] and the FMO method [ 47 ] as the main methods for explaining the biological activity and visualized the MEP surface [ 45 ]. We also performed the PIE analysis [ 33 ] for verification of the FMO method and then analyzed the electron density.…”

Section: Discussionmentioning

confidence: 99%

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A Study on the Effect of the Substituent against PAK4 Inhibition Using In Silico Methods

Yoon

Chai²,

Kim³

et al. 2022

IJMS

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The intrinsic inductive properties of atoms or functional groups depend on the chemical properties of either electron-withdrawing groups (EWGs) or electron-donating groups (EDGs). This study aimed to evaluate in silico methods to determine whether changes in chemical properties of the compound by single atomic substitution affect the biological activity of target proteins and whether the results depend on the properties of the functional groups. We found an imidazo[4,5-b]pyridine-based PAK4 inhibitor, compound 1, as an initial hit compound with the well-defined binding mode for PAK4. In this study, we used both experimental and in silico methods to investigate the effect of atomic substitution on biological activity to optimize the initial hit compound. In biological assays, in the case of EWG, as the size of the halogen atom became smaller and the electronegativity increased, the biological activity IC50 value ranged from 5150 nM to inactive; in the case of EDG, biological activity was inactive. Furthermore, we analyzed the interactions of PAK4 with compounds, focusing on the hinge region residues, L398 and E399, and gatekeeper residues, M395 and K350, of the PAK4 protein using molecular docking studies and fragment molecular orbital (FMO) methods to determine the differences between the effect of EWG and EDG on the activity of target proteins. These results of the docking score and binding energy did not explain the differences in biological activity. However, the pair-interaction energy obtained from the results of the FMO method indicated that there was a difference in the interaction energy between the EWG and EDG in the hinge region residues, L398 and E399, as well as in M395 and K350. The two groups with different properties exhibited opposite electrostatic energy and charge transfer energy between L398 and E399. Additionally, we investigated the electron distribution of the parts interacting with the hinge region by visualizing the molecular electrostatic potential (MEP) surface of the compounds. In conclusion, we described the properties of functional groups that affect biological activity using an in silico method, FMO.

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Section: Discussionmentioning

confidence: 99%

“…After the protein and compound preparation step, molecular docking studies were performed on the processed structures using the LigandFit module [ 46 ] of receptor-ligand interactions tools of Discovery Studio 2021 (BIOVIA, San Diego, CA, USA). The binding site was defined based on the co-crystallized ligand.…”

Section: Methodsmentioning

confidence: 99%

A Study on the Effect of the Substituent against PAK4 Inhibition Using In Silico Methods

Yoon

Chai²,

Kim³

et al. 2022

IJMS

View full text Add to dashboard Cite

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“…The molecular mechanics involve X-ray crystallographic studies to understand the 3D conformation of the molecule and the ability of the molecule to bind to the target/receptor. Molecular mechanics are inexpensive and easy to manage and are used to reproduce molecular confirmations matching and adjusting the bond lengths, bond angles, and torsion angles to equilibrium values to the one it has been designed to bind/attach 60 . The QSAR study is a technique that quantifies the anatomical and biological properties of the molecules/ligands/proteins.…”

Section: Molecular Superimposition and Molecular Mechanics Involved I...mentioning

confidence: 99%

The Current Perspectives in Clinical Research: Computer-Assisted Drug Designing, Ethics, and Good Clinical Practice

et al. 2022

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In the era of emerging microbial and non-communicable diseases and re-emerging microbial infections, the medical fraternity and the public are plagued by under-preparedness. It is evident by the severity of the Coronavirus disease (COVID-19) pandemic that novel microbial diseases are a challenge and are challenging to control. This is mainly attributed to the lack of complete knowledge of the novel microbe’s biology and pathogenesis and the unavailability of therapeutic drugs and vaccines to treat and control the disease. Clinical research is the only answer utilizing which can handle most of these circumstances. In this review, we highlight the importance of computer-assisted drug designing (CADD) and the aspects of molecular docking, molecular superimposition, 3D-pharmacophore technology, ethics, and good clinical practice (GCP) for the development of therapeutic drugs, devices, and vaccines.

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“…The compounds were then evaluated for blood-brain barrier (BBB) penetration, HIA (Human Intestinal Absorption), and AMES monitoring. Predicting the ADMET characteristics is an important predictor of the drug candidate's behavior, toxicity level, and fate in the human body [34,35]. It indicates the possibility of the candidate's capacity to enter the intestinal absorption, metabolism, blood-brain barrier, subcellular localization, and, most importantly, the potential for injury to the body.…”

Section: Solvent Accessible Surface Area (Sasa)mentioning

confidence: 99%

Screening of Phytochemicals against Osteoporosis: Molecular Docking and Simulation-Based Computational Approaches

Aloufi¹

2022

Int J Pharm Res Allied Sci

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Osteoporosis is a skeletal disorder characterized by low bone mineral density and microarchitecture deterioration, which may result in fragility and fracture risk. Osteoporosis mostly affects postmenopausal women but elderly men may also be affected. It is a silent disease and reveals at the time of fracture. It is the most prevalent bone disease in the world. Currently, there is no cure available for osteoporosis. Through a literature survey, an association is found between the overexpressed genes and osteoporosis. E2 ubiquitin ligase TRAF3IP2 is reported to be overexpressed in osteoporotic vertebral fractures. This study was designed to develop the drug targets against osteoporosis with more therapeutic efficacy and least side effects. Proteins of the overexpressed genes were searched from the PDB database. After inhibitory protein was searched from literature and used as reference protein. A library of 13000 phytochemicals was docked against novel drug targets through Molecular Operating Environment (MOE). Absorption, distribution, metabolism, excretion, and toxicological analysis were done through ADMETsar. After careful analysis top four compounds Adenosine, 2'-deoxy-, 2-Amino-1hydroxyoctadecan-3-one, (3,5-Dihydroxyoxolan-2-yl) methyl dihydrogen phosphate and 2-

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Molecular modeling in drug discovery

Cited by 163 publications

References 216 publications

A Study on the Effect of the Substituent against PAK4 Inhibition Using In Silico Methods

A Study on the Effect of the Substituent against PAK4 Inhibition Using In Silico Methods

The Current Perspectives in Clinical Research: Computer-Assisted Drug Designing, Ethics, and Good Clinical Practice

Screening of Phytochemicals against Osteoporosis: Molecular Docking and Simulation-Based Computational Approaches

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