Last update 01 Nov 2024

DTYMK

Last update 01 Nov 2024

Basic Info

Synonyms

CDC8, deoxythymidylate kinase, dTMP kinase

+ [4]

Introduction

Catalyzes the phosphorylation of thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), the immediate precursor for the DNA building block dTTP, with ATP as the preferred phosphoryl donor in the presence of Mg(2+).

Drugs associated with DTYMK

TK-666

Target

DTYMK

Mechanism

DTYMK inhibitors

Active Org.

AstraZeneca PLC

Originator Org.

AstraZeneca PLC

Active Indication

Gram-Positive Bacterial Infections

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

TMPK inhibitors(Ghent University)

Target

DTYMK

Mechanism

DTYMK inhibitors

Active Org.

Ghent University

Originator Org.

Ghent University

Active Indication

Mycobacterium Tuberculosis, Susceptibility to Infection By

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with DTYMK

100 Translational Medicine associated with DTYMK

0 Patents (Medical) associated with DTYMK

586

Literatures (Medical) associated with DTYMK

31 Dec 2024·Journal of Enzyme Inhibition and Medicinal Chemistry

Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPK mt ) inhibition activity and molecular modelling studies

Article

Author: Mahran, Mona A. ; Shehat, Michael G. ; Atta, Amal ; Fahmy, Salwa ; Sriram, Dharmarajan ; Labouta, Ibrahim M. ; El-Shoukrofy, Mai S.

New Biginelli adducts were rationalised, via the introduction of selected anti-tubercular (TB) pharmacophores into the dihydropyrimidine (DHPM) ring of deoxythymidine monophosphate (dTMP), the natural substrate of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Repurposing was one of the design rationale strategies for some selected mimics of the designed compounds. The anti-TB activity was screened against the Mtb H₃₇Rv strain where 11a was superior to ethambutol (EMB), and was 9-fold more potent than pyrazinamide (PZA). Additionally, compounds 11b, 4a, 4b, 13a, 13b and 14a elicited higher anti-TB activity than PZA, showing better safety profiles than EMB against RAW 264.7 cells' growth. The in vitro TMPKmt inhibition assay released compounds 11a, 11b and 13b as the most potent inhibitors. Docking studies presumed the binding modes and molecular dynamics (MD) simulation revealed the dynamic stability of 11a-TMPKmt complex over 100 ns. In silico prediction of the chemo-informatics properties of the most active compounds was conducted.

12 Oct 2024·Journal of Biomolecular Structure and Dynamics

In silico design based on quantum chemical, molecular docking studies and ADMET predictions of ciprofloxacin derivatives as novel potential antibacterial and antimycrobacterium agents

Article

Author: Benchouk, Wafaa ; Benselama, Wafa

Drug designing and development is an important area of research for pharmaceutical companies and chemical scientists. In this paper, we report the prediction of new ciprofloxacin derivatives by quantum chemical, molecular docking studies and pharmacokinetic properties. Theoretical studies were performed by geometry optimization computation using B3LYP level at 6-311 G (d,p) basis set. The absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters were predicted and the result show that all compounds have a great ADMET profile. To study the antibacterial, anti-Mycobacterium tuberculosis activities, ciprofloxacin and its derivatives were interacted with the proteins: Thymidylate Kinase (PDB: 4QGG), Biotin carboxylase (PDB: 3JZF) and β-lactamase BlaC (PDB: 3N7W). The results of the docking studies indicate that one pharmacophore designed presents a great inhibition behavior against gram-positive organism (4QGG) and significant interactions observed between the compound and ARG48, GLN101, ARG105 and GLU37 residues of 4QGG. Also, another derivative designed present the best inhibition against gram-negative organism (3JZF) several interactions were noticed between the compound and GLY165, ILE287, LEU278, HIS236, HIS209, MET169 and LYS159 residues of (3JZF). As well as, one designed candidate is good inhibitors for β-lactamase (3N7W) multiple no bonded interactions were observed between the compound and SER84, ILE117, ASN186, LYS87, ARG187, ASN186 and THR251 residues of(3N7W). Molecular dynamics (MD) simulation study was also performed for 100 ns to confirm the stability behaviour of the main protein and inhibitor complexes. The MD simulation study validated the stability of three compounds in the protein binding pocket as potent binders. Natural bonding orbital analysis, reactivity indices and molecular electrostatic potential were carried out. The research finding of this study can be helpful to design a new potent antibacterial, antimycrobacterium candidate's drugs that will serve as the basis for future in vitro and in vivo research.Communicated by Ramaswamy H. Sarma.

01 Aug 2024·Molecular Diversity

Identification of mycobacterial Thymidylate kinase inhibitors: a comprehensive pharmacophore, machine learning, molecular docking, and molecular dynamics simulation studies

Article

Author: Pawar, Surbhi Pravin ; Dahlous, Kholood A ; Patil, Pritee Chunarkar ; Chikhale, Rupesh V ; Kolpe, Mahima Sudhir ; Bhowmick, Shovonlal ; Mohammad, Saikh ; Shinde, Omkar Dilip

AbstractThymidylate kinase (TMK) is a pivotal enzyme in Mycobacterium tuberculosis (Mtb), crucial for phosphorylating thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), thereby playing a critical role in DNA biosynthesis. Dysregulation or inhibition of TMK activity disrupts DNA replication and cell division, making it an attractive target for anti-tuberculosis drug development. In this study, the statistically validated pharmacophore mode was developed from a set of known TMK inhibitors. Further, the robust pharmacophore was considered for screening the Enamine database. The chemical space was reduced through multiple molecular docking approaches, pharmacokinetics, and absolute binding energy estimation. Two different molecular docking algorithms favor the strong binding affinity of the proposed molecules towards TMK. Machine learning-based absolute binding energy also showed the potentiality of the proposed molecules. The binding interactions analysis exposed the strong binding affinity between the proposed molecules and active site amino residues of TMK. Several statistical parameters from all atoms MD simulation explained the stability between proposed molecules and TMK in the dynamic states. The MM-GBSA approach also found a strong binding affinity for each proposed molecule. Therefore, the proposed molecules might be crucial TMK inhibitors for managing Mtb inhibition subjected to in vitro/in vivo validations.

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DTYMK

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