Fundamentals of molecular modeling in drug design

Tripathi, Manish Kumar; Ahmad, Shaban; Tyagi, Rashmi; Dahiya, Vandana; Yadav, Manoj Kumar

doi:10.1016/b978-0-323-90608-1.00001-0

Cited by 32 publications

(10 citation statements)

References 47 publications

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“…A molecule’s higher overall energy indicates that it is less stable and more reactive (Rahman et al 2020). Additionally, free energy is a crucial parameter for describing the interactions of binding partners, where both the sign and magnitude are crucial for expressing the likelihood of bimolecular events, and higher negative values denote superior thermodynamic features (Tripathi et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

Computational Assessment of Aromatase: Unmasking Therapeutic Avenues for Female Hormonal Disorders

Koirala,

Magar,

Yadav

et al. 2023

Preprint

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Women of reproductive age widely experience the physical, mental, and emotional effects of hormonal imbalances. The levels of two hormones, estrogen, and progesterone, were particularly high. When these two hormones are unbalanced, symptoms such as irregular menstrual cycles, pelvic pain, and uterine fibroids can appear. Statistics show that 80 percent of women have hormonal imbalances. The creation of novel disease-containing drug candidates may be facilitated by computer-aided drug design (CADD), as many drugs and surgical treatments have unique adverse effects. Achieving good data coverage requires an optimized process for protein identification and enhanced selection techniques for medicinal compounds, including their metabolic characterization. In this study, aromatase is the prioritized protein that acted as a rate-limiting enzyme in steroidogenesis. To maintain its expression and regulation to control estrogen production, natural compounds were retrieved from the ZINC15 database through ADME/TOX property filtration. Compound B, specifically designated as (1R,3S,6S,7S,10S,11R)-7-[(dimethylamino)methyl]-3,12-dimethyl-2,9-dioxatetracyclo [9.3.0.01,3.06,10] tetradec-12-en-8-one, exhibits remarkable therapeutic potential, as evidenced by its inability to inhibit S-adenosyl methionine (SAM) biosynthesis, the observed stability of molecular interactions based on Density Functional Theory (DFT), and a favorable energy gap between molecular orbital stages. This research can be employed as a utility module for fast screening of drug-like molecules and taking these leads forward to clinical trials, assessing their value as potential suitors for drug repurposing against female hormonal disorders.

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Section: Resultsmentioning

confidence: 99%

Computational Assessment of Aromatase: Unmasking Therapeutic Avenues for Female Hormonal Disorders

Koirala,

Magar,

Yadav

et al. 2023

Preprint

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“…irregularities that often require correction or refinement to ensure accuracy and energy minimisation may be necessary to optimise the protein's geometry [29][30][31]. PDBID: 5VBN and 6UJB contain chains A, B, E, and F of proteins, solvents, and metals/ions, and 6NT9 contains chains A, B, and ligands [6][7][8].…”

Section: Plos Onementioning

confidence: 99%

Delineating Pixantrone Maleate’s adroit activity against cervical cancer proteins through multitargeted docking-based MM\GBSA, QM-DFT and MD simulation

Almasoudi,

Nahari,

Alhazmi

et al. 2023

PLoS ONE

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Cervical cancer poses a substantial worldwide health challenge, especially in low- and middle-income nations, caused by high-risk types of human papillomavirus. It accounted for a significant percentage of cancer-related deaths among women, particularly in areas with limited healthcare resources, necessitating innovative therapeutic approaches, and single-targeted studies have produced significant results, with a considerable chance of developing resistance. Therefore, the multitargeted studies can work as a beacon of hope. This study is focused on performing the multitargeted molecular docking of FDA-approved drugs with the three crucial proteins TBK1, DNA polymerase epsilon, and integrin α-V β-8 of cervical cancer. The docking studies using multisampling algorithms HTVS, SP, and XP reveal Pixantrone Maleate (DB06193) as a multitargeted inhibitor with docking scores of -8.147, -8.206 and -7.31 Kcal/mol and pose filtration with MM\GBSA computations with scores -40.55, -33.67, and -37.64 Kcal/mol. We also have performed QM-based DFT and pharmacokinetics studies of the compound and compared it with the standard values, which results in the compound being entirely suitable against cervical cancer proteins. The interaction fingerprints have revealed that PHE, VAL, SER and ALA are the residues among most interactions. We also explore the stability of the multitargeted potential of Pixantrone Maleate through 100ns MD simulations and investigate the RMSD, RMSF and intermolecular interactions between all three proteins-ligand complexes. All computational studies favour Pixantrone Maleate as a multitargeted inhibitor of the TBK1, DNA polymerase epsilon, and integrin α-V β-8 and can be validated experimentally before use.

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“…Despite extensive research efforts and advancements in medical science, lung cancer poses a significant public health burden. One of the defining characteristics of lung cancer is its complex molecular landscape [ 8 , 9 , 10 ]. Unlike some other cancers, lung cancer is not a monolithic disease.…”

Section: Introductionmentioning

confidence: 99%

Delineated 3-1-BenCarMethInYlPro-Phosphonic Acid’s Adroit Activity against Lung Cancer through Multitargeted Docking, MM\GBSA, QM-DFT and Multiscale Simulations

Hakami,

Hazazi,

Albloui

et al. 2024

IJMS

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Lung cancer is a pervasive and challenging disease with limited treatment options, with global health challenges often present with complex molecular profiles necessitating the exploration of innovative therapeutic strategies. Single-target drugs have shown limited success due to the heterogeneity of this disease. Multitargeted drug designing is imperative to combat this complexity by simultaneously targeting multiple target proteins and pathways, which can enhance treatment efficacy and overcome resistance by addressing the dynamic nature of the disease and stopping tumour growth and spread. In this study, we performed the molecular docking studies of Drug Bank compounds with a multitargeted approach against crucial proteins of lung cancer such as heat shock protein 5 (BIP/GRP78) ATPase, myosin 9B RhoGAP, EYA2 phosphatase inhibitor, RSK4 N-terminal kinase, and collapsin response mediator protein-1 (CRMP-1) using HTVS, SP with XP algorithms, and poses were filtered using MM\GBSA which identified [3-(1-Benzyl-3-Carbamoylmethyl-2-Methyl-1h-Indol-5-Yloxy)-Propyl-]-Phosphonic Acid (3-1-BenCarMethIn YlPro-Phosphonic Acid) (DB02504) as multitargeted drug candidate with docking and MM\GBSA score ranges from −5.83 to −10.66 and −7.56 to −50.14 Kcal/mol, respectively. Further, the pharmacokinetic and QM-based DFT studies have shown complete acceptance results, and interaction fingerprinting reveals that ILE, GLY, VAL, TYR, LEU, and GLN were among the most interacting residues. The 100 ns MD simulation in the SPC water model with NPT ensemble showed stable performance with deviation and fluctuations <2 Å with huge interactions, making it a promising multitargeted drug candidate; however, experimental studies are needed before use.

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Fundamentals of molecular modeling in drug design

Cited by 32 publications

References 47 publications

Computational Assessment of Aromatase: Unmasking Therapeutic Avenues for Female Hormonal Disorders

Computational Assessment of Aromatase: Unmasking Therapeutic Avenues for Female Hormonal Disorders

Delineating Pixantrone Maleate’s adroit activity against cervical cancer proteins through multitargeted docking-based MM\GBSA, QM-DFT and MD simulation

Delineated 3-1-BenCarMethInYlPro-Phosphonic Acid’s Adroit Activity against Lung Cancer through Multitargeted Docking, MM\GBSA, QM-DFT and Multiscale Simulations

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