Abstract:IntroductionMonkeypox is a zoonotic disease caused by brick-shaped enveloped monkeypox (Mpox) virus that belongs to the family of ancient viruses known as Poxviridae. Subsequently, the viruses have been reported in various countries. The virus is transmitted by respiratory droplets, skin lesions, and infected body fluids. The infected patients experience fluid-filled blisters, maculopapular rash, myalgia, and fever. Due to the lack of effective drugs or vaccines, there is a need to identify the most potent and… Show more
“…The compound DB16335, with a glide score of-9.7 kcal/mol and binding affinities of-60.07 kcal/mol and-16.06 kcal/mol from MM-GBSA and Molecular Mechanics Poisson-Boltzmann Surface Area method (MM-PBSA) assays, respectively, demonstrated stability over 75 ns of a 300 ns MD simulation. It maintained a backbone atom RMSD of 2.0 Å and interacted with residues including Asp13, Thr18, and Arg41, forming hydrogen bonds with Phe38, and Glu142, among others, effectively inhibiting the monkeypox virus [25]. These findings underscore the potential of the benzylidene amino phenol derivative as a potent inhibitor of HaTMK, similar to the efficacy observed in the monkeypox study, thus highlighting its promise for colon cancer treatment through HaTMK inhibition.…”
Objective: Thymidylate Kinase (TMK) plays a crucial role in bacterial DNA synthesis by catalyzing the phosphorylation of Deoxythymidine Monophosphate (dTMP) to form Deoxythymidine Diphosphate (dTDP). Consequently, this enzyme emerges as a promising target for developing novel anti-cancer drugs. However, no anti-cancer drugs have been reported for this target until now.
Methods: Ligands obtained from Benzylidene derivatives were examined for their potency by using molecular docking by glide module, Qikprop screening of Absorption, Distribution, Metabolism, and Excretion (ADME) study, and prime Molecular Mechanics in Generalized Bond Surface Area study (MM-GBSA) by binding free energy. Hereafter, a Molecular Dynamic (MD) simulation was performed at 100 ns to assess the stability of the potential ligand as a Human TMK (HaTMK) inhibitor.
Results: These ten molecules showed good binding affinity and hydrogen and hydrophobic bond interactions with Arg150, Phe42, and Phe72 in the HaTMK enzyme (PDB id: 1E2D). Among them, trichloro-6-(((4-hydroxyphenyl)imino)methyl)phenol molecule had a high XP-docking score of (−7.87 kcal/mol), based on extra-precision data. Prime MM-GBSA studies also showed promising binding affinities i.e., ΔBind (-34.59 kcal/mol), ΔLipo (-13.92 kcal/mol), and ΔVdW (-34.42 kcal/mol). Arg76 and Phe72 residues maintained constant interactions with the ligand during Molecular Dynamics (MD) simulation. This ligand showed a potential binding affinity for the TMK target.
Conclusion: The trichloro-6-(((4-hydroxyphenyl)imino)methyl)phenol ligand has active sites, namely benzene ring, benzylidene, and oxygen group, which actively participate in interaction with the protein of HaTMK, thus indicating good potential activity as the inhibitor of HaTMK to treat colon cancer.
“…The compound DB16335, with a glide score of-9.7 kcal/mol and binding affinities of-60.07 kcal/mol and-16.06 kcal/mol from MM-GBSA and Molecular Mechanics Poisson-Boltzmann Surface Area method (MM-PBSA) assays, respectively, demonstrated stability over 75 ns of a 300 ns MD simulation. It maintained a backbone atom RMSD of 2.0 Å and interacted with residues including Asp13, Thr18, and Arg41, forming hydrogen bonds with Phe38, and Glu142, among others, effectively inhibiting the monkeypox virus [25]. These findings underscore the potential of the benzylidene amino phenol derivative as a potent inhibitor of HaTMK, similar to the efficacy observed in the monkeypox study, thus highlighting its promise for colon cancer treatment through HaTMK inhibition.…”
Objective: Thymidylate Kinase (TMK) plays a crucial role in bacterial DNA synthesis by catalyzing the phosphorylation of Deoxythymidine Monophosphate (dTMP) to form Deoxythymidine Diphosphate (dTDP). Consequently, this enzyme emerges as a promising target for developing novel anti-cancer drugs. However, no anti-cancer drugs have been reported for this target until now.
Methods: Ligands obtained from Benzylidene derivatives were examined for their potency by using molecular docking by glide module, Qikprop screening of Absorption, Distribution, Metabolism, and Excretion (ADME) study, and prime Molecular Mechanics in Generalized Bond Surface Area study (MM-GBSA) by binding free energy. Hereafter, a Molecular Dynamic (MD) simulation was performed at 100 ns to assess the stability of the potential ligand as a Human TMK (HaTMK) inhibitor.
Results: These ten molecules showed good binding affinity and hydrogen and hydrophobic bond interactions with Arg150, Phe42, and Phe72 in the HaTMK enzyme (PDB id: 1E2D). Among them, trichloro-6-(((4-hydroxyphenyl)imino)methyl)phenol molecule had a high XP-docking score of (−7.87 kcal/mol), based on extra-precision data. Prime MM-GBSA studies also showed promising binding affinities i.e., ΔBind (-34.59 kcal/mol), ΔLipo (-13.92 kcal/mol), and ΔVdW (-34.42 kcal/mol). Arg76 and Phe72 residues maintained constant interactions with the ligand during Molecular Dynamics (MD) simulation. This ligand showed a potential binding affinity for the TMK target.
Conclusion: The trichloro-6-(((4-hydroxyphenyl)imino)methyl)phenol ligand has active sites, namely benzene ring, benzylidene, and oxygen group, which actively participate in interaction with the protein of HaTMK, thus indicating good potential activity as the inhibitor of HaTMK to treat colon cancer.
“…Using the AMBER version 2022 (Schrödinger, San Francisco, CA, USA) package [24], MD simulation was carried out for 200 ns to examine the stability and dynamic evaluation of the best complexes. For protein and ligand molecules, the FF19SB force field and the general amber force field (GAFF), respectively, were used [50]. Na + ions were added to counteract the effects of any charge, and energy reduction was accomplished in two phases (using the steepest descent and conjugate gradient methods) [51].…”
Single-point mutations in the Kirsten rat sarcoma (KRAS) viral proto-oncogene are the most common cause of human cancer. In humans, oncogenic KRAS mutations are responsible for about 30% of lung, pancreatic, and colon cancers. One of the predominant mutant KRAS G12D variants is responsible for pancreatic cancer and is an attractive drug target. At the time of writing, no Food and Drug Administration (FDA) approved drugs are available for the KRAS G12D mutant. So, there is a need to develop an effective drug for KRAS G12D. The process of finding new drugs is expensive and time-consuming. On the other hand, in silico drug designing methodologies are cost-effective and less time-consuming. Herein, we employed machine learning algorithms such as K-nearest neighbor (KNN), support vector machine (SVM), and random forest (RF) for the identification of new inhibitors against the KRAS G12D mutant. A total of 82 hits were predicted as active against the KRAS G12D mutant. The active hits were docked into the active site of the KRAS G12D mutant. Furthermore, to evaluate the stability of the compounds with a good docking score, the top two complexes and the standard complex (MRTX-1133) were subjected to 200 ns MD simulation. The top two hits revealed high stability as compared to the standard compound. The binding energy of the top two hits was good as compared to the standard compound. Our identified hits have the potential to inhibit the KRAS G12D mutation and can help combat cancer. To the best of our knowledge, this is the first study in which machine-learning-based virtual screening, molecular docking, and molecular dynamics simulation were carried out for the identification of new promising inhibitors for the KRAS G12D mutant.
In 2022, a global outbreak of Mpox (formerly monkeypox) occurred in various countries across Europe and America and rapidly spread to more than 100 countries and regions. The World Health Organization declared the outbreak to be a public health emergency of international concern due to the rapid spread of the Mpox virus. Consequently, nations intensified their efforts to explore treatment strategies aimed at combating the infection and its dissemination. Nevertheless, the available therapeutic options for Mpox virus infection remain limited. So far, only a few numbers of antiviral compounds have been approved by regulatory authorities. Given the high mutability of the Mpox virus, certain mutant strains have shown resistance to existing pharmaceutical interventions. This highlights the urgent need to develop novel antiviral drugs that can combat both drug resistance and the potential threat of bioterrorism. Currently, there is a lack of comprehensive literature on the pathophysiology and treatment of Mpox. To address this issue, we conducted a review covering the physiological and pathological processes of Mpox infection, summarizing the latest progress of anti-Mpox drugs. Our analysis encompasses approved drugs currently employed in clinical settings, as well as newly identified small-molecule compounds and antibody drugs displaying potential antiviral efficacy against Mpox. Furthermore, we have gained valuable insights from the process of Mpox drug development, including strategies for repurposing drugs, the discovery of drug targets driven by artificial intelligence, and preclinical drug development. The purpose of this review is to provide readers with a comprehensive overview of the current knowledge on Mpox.
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