Updates on Drug Designing Approach Through Computational Strategies: a Review

Azad, Iqbal; Khan, Tahmeena; Ahmad, Naseem; Khan, Abdul Rahman; Akhter, Yusuf

doi:10.2144/fsoa-2022-0085

Cited by 11 publications

(7 citation statements)

References 268 publications

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“…32 Through computer screening and prediction techniques, it has become increasingly feasible to identify potential drug candidates and explore novel target strategies with enhanced efficacy. 33 Therefore, we used a computational approach to identify the structural properties of Lys-PP. As a result, we confirmed Lys-PP possessed a substantial abundance of lysine (K) (17.9%) and arginine (R) (12.8%), thereby conferring a positively charged nature, as indicated by their predicted basic isoelectric point.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Significant progress has been made in the field of computational technology, enabling the repurposing of existing drugs, de novo design of drug candidates, and the discovery of more effective strategies for targeting diseases . Through computer screening and prediction techniques, it has become increasingly feasible to identify potential drug candidates and explore novel target strategies with enhanced efficacy . Therefore, we used a computational approach to identify the structural properties of Lys-PP.…”

Section: Discussionmentioning

confidence: 99%

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Lysine-Rich Polypeptide Modulates Forkhead Box O3 and Phosphoinositide 3-Kinase-Protein Kinase B Pathway To Induce Apoptosis in Breast Cancer

Dhandapani,

Choi,

Chung

et al. 2024

ACS Pharmacol. Transl. Sci.

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The PI3K/AKT/FOXO3 pathway is one of the most frequently involved signaling pathways in cancer, including breast cancer. Therefore, we synthesized a novel lysine-rich polypeptide (Lys-PP) using de novo assembly method and evaluated its anticancer effect. We characterized the structural and physicochemical properties of Lys-PP using various techniques. Later, we used integrated approaches such as in silico, in vitro, and in vivo analysis to confirm the anticancer and therapeutic effect of Lys-PP. First, RNA sequencing suggests Lys-PP disrupted the central carbon metabolic pathway through the modulation of prolactin signaling. Additionally, docking analysis also confirmed the significant association of PI3K/AKT and FOXO3 pathway to induce an apoptotic effect on cancer. Second, Lys-PP exhibited a significant cytotoxicity effect against MDA-MB-231 but no cytotoxic effects on RAW 264.7 and HEK-293, respectively. The cytotoxic effect of Lys-PP-induced apoptosis by an increase in FOXO3a protein expression and a decrease in PI3K/AKT pathway was confirmed by quantitative real-time polymerase chain reaction, immunoblotting, and fluorescent microscopy. Later, immunohistochemistry and hematoxylin and eosin staining on MDA-MD-231 showed increased FOXO3a expression and cell death in the xenograft mice model. Further, liver function, metabolic health, or lipid profile upon Lys-PP showed the absence of significant modulation in the biomarkers except for kidney-related biomarkers. Overall, our comprehensive study provides the first evidence of Lys-PP antibreast cancer action, which could serve as a potential treatment in an alternative or complementary medicine practice.

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Section: ■ Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lysine-Rich Polypeptide Modulates Forkhead Box O3 and Phosphoinositide 3-Kinase-Protein Kinase B Pathway To Induce Apoptosis in Breast Cancer

Dhandapani,

Choi,

Chung

et al. 2024

ACS Pharmacol. Transl. Sci.

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“…[ 21 ] Molecular docking is a theoretical simulation technology which often used to study inter-molecular interactions and predict their binding modes and affinities for further new drug discovery. [ 22 , 23 ]…”

Section: Introductionmentioning

confidence: 99%

Tripterygium wilfordii Hook.f induced kidney injury through mediating inflammation via PI3K-Akt/HIF-1/TNF signaling pathway: A study of network toxicology and molecular docking

Yang,

Wang,

et al. 2024

Medicine

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We intend to explore potential mechanisms of Tripterygium wilfordii Hook.f (TwHF) induced kidney injury (KI) using the methods of network toxicology and molecular docking. We determined TwHF potential compounds with its targets and KI targets, obtained the TwHF induced KI targets after intersecting targets of TwHF and KI. Then we conducted protein-protein interaction (PPI) network, gene expression analysis, gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis to explore the mechanism of TwHF-induced KI. Finally we conducted molecular docking to verify the core toxic compounds and the targets. We obtained 12 TwHF toxic compounds and 62 TwHF-induced KI targets. PPI network, gene expression analysis and GO function enrichment analysis unveiled the key biological process and suggested the mechanism of TwHF-induced KI might be associated with inflammation, immune response, hypoxia as well as oxidative stress. KEGG pathway enrichment analysis indicated PI3K-Akt signaling pathway, HIF-1 signaling pathway and TNF signaling pathway were key signaling pathways of TwHF induced KI. Molecular docking showed that the binding energy of core targets and toxic compounds was all less than −6.5 kcal/mol that verified the screening ability of network pharmacology and provided evidence for modifying TwHF toxic compounds structure. Through the study, we unveiled the mechanism of TwHF induce KI that TwHF might activate PI3K-Akt signaling pathway as well as TNF signaling pathway to progress renal inflammation, mediate hypoxia via HIF-1 signaling pathway to accelerate inflammatory processes, and also provided a theoretical basis for modifying TwHF toxic compounds structure as well as supported the follow-up research.

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“…The advent of computational chemistry and advancements in synthetic methodologies have brought about a paradigm shift in compound discovery and optimization [5][6][7]. In recent years, in silico reaction-based enumeration has gained prominence, offering a novel solution to overcome the limitations inherent in traditional HTS methods [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

AI-driven drug discovery: identification and optimization of ALDH3A1 selective inhibitors with nanomolar activity

Jain,

Yasgar,

Dalal

et al. 2024

Preprint

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In the field of medicinal chemistry, the discovery of novel compounds with therapeutic potential is of utmost importance. However, the conventional approach to drug discovery, relying on high-throughput screening (HTS), encounters limitations such as reagent availability and labor costs. Although a hit-finding campaign starts with a virtual screen of millions of compounds, the hit-to-lead and lead optimization stages often require designing, synthesizing, and profiling thousands of analogs before selecting clinical candidates. Recent advances offer an innovative solution - the virtual generation of billions of synthetically feasible compounds with an impressive 80% success rate for synthesis. This breakthrough has the potential to significantly expand the chemical space available for purchase and experimental validation, bringing about a revolution in the field. Our study presents a comprehensive approach to compound discovery and optimization, harnessing quantitative high-throughput screening (qHTS), chemical databases, and reaction-based enumeration. To further enhance the synthesis process and gain deeper insights into compound formation, we utilize the Reaction Cookbook from Biosolveit, which comprises reaction SMARTs for around 300 chemical reactions. By employing this wide range of reactions, we aim to uncover the full spectrum of a chemotype's potential and customize its structure to optimize desired properties. As an illustration of this approach, our work on the ALDH3A1 project resulted in the synthesis of 50 compounds, with 21 of them exhibiting activity (negative curve class values; hit-rate ~42%). Among these active compounds, 6 displayed IC50 values lower than 30 µM and efficacy values less than -50%, with the most potent compound achieving an impressive potency of 447 nM. This study demonstrates the successful synergy between in-silico reaction-based analogs enumeration, molecular modeling and AI/ML-based techniques in identifying compounds with improved biological activity, offering promising prospects for the development of ALDH3A1-targeting agents as potential cancer therapeutics. Computational workflows developed in this study can be used for similar target-based drug discovery campaigns.

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Updates on Drug Designing Approach Through Computational Strategies: a Review

Cited by 11 publications

References 268 publications

Lysine-Rich Polypeptide Modulates Forkhead Box O3 and Phosphoinositide 3-Kinase-Protein Kinase B Pathway To Induce Apoptosis in Breast Cancer

Lysine-Rich Polypeptide Modulates Forkhead Box O3 and Phosphoinositide 3-Kinase-Protein Kinase B Pathway To Induce Apoptosis in Breast Cancer

Tripterygium wilfordii Hook.f induced kidney injury through mediating inflammation via PI3K-Akt/HIF-1/TNF signaling pathway: A study of network toxicology and molecular docking

AI-driven drug discovery: identification and optimization of ALDH3A1 selective inhibitors with nanomolar activity

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