Integration of ligand and structure based approaches for identification of novel MbtI inhibitors in Mycobacterium tuberculosis and molecular dynamics simulation studies

Maganti, Lakshmi; Grandhi, Pradeep; Ghoshal, Nanda

doi:10.1016/j.jmgm.2016.09.004

Cited by 5 publications

(2 citation statements)

References 28 publications

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“…Therefore, we employed a ligand- and structure-based pharmacophore modeling approach complexed with a series of other computational methods as a valuable strategy for targeting CDK7 inhibition ( Figure 1 ). The combination approach can retrieve more drug-like compounds from databases as both works on different principles [ 72 , 73 ]. To our knowledge, this is the first pharmacophore-based study to search for novel and selective CDK7 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Identification of CDK7 Inhibitors from Natural Sources Using Pharmacoinformatics and Molecular Dynamics Simulations

et al. 2021

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The cyclin-dependent kinase 7 (CDK7) plays a crucial role in regulating the cell cycle and RNA polymerase-based transcription. Overexpression of this kinase is linked with various cancers in humans due to its dual involvement in cell development. Furthermore, emerging evidence has revealed that inhibiting CDK7 has anti-cancer effects, driving the development of novel and more cost-effective inhibitors with enhanced selectivity for CDK7 over other CDKs. In the present investigation, a pharmacophore-based approach was utilized to identify potential hit compounds against CDK7. The generated pharmacophore models were validated and used as 3D queries to screen 55,578 natural drug-like compounds. The obtained compounds were then subjected to molecular docking and molecular dynamics simulations to predict their binding mode with CDK7. The molecular dynamics simulation trajectories were subsequently used to calculate binding affinity, revealing four hits—ZINC20392430, SN00112175, SN00004718, and SN00262261—having a better binding affinity towards CDK7 than the reference inhibitors (CT7001 and THZ1). The binding mode analysis displayed hydrogen bond interactions with the hinge region residues Met94 and Glu95, DFG motif residue Asp155, ATP-binding site residues Thr96, Asp97, and Gln141, and quintessential residue outside the kinase domain, Cys312 of CDK7. The in silico selectivity of the hits was further checked by docking with CDK2, the close homolog structure of CDK7. Additionally, the detailed pharmacokinetic properties were predicted, revealing that our hits have better properties than established CDK7 inhibitors CT7001 and THZ1. Hence, we argue that proposed hits may be crucial against CDK7-related malignancies.

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Section: Discussionmentioning

confidence: 99%

Identification of CDK7 Inhibitors from Natural Sources Using Pharmacoinformatics and Molecular Dynamics Simulations

et al. 2021

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“…Molecular dynamics stimulation affirmed that the inhibitors represented stability in active cavity of the protein by a minimal confirmational change in the surrounding amino acids. 54 Zang and co-workers published chorismate utilizing enzymes transition state inhibitors synthesis. The replacement of hydroxyl functionality with amino functionality yielded compound 6 which was disqualified due to its non MbtI inhibitory activity at 100 µM that was found to be very low.…”

Section: Mbti Inhibitors Are Classified In Two Main Types Based On Th...mentioning

confidence: 99%

Molecular Insights into Salicylate Synthase: From Medicinal Chemistry Perspective

Bire,

Walhekar,

Makane

et al. 2024

Ind. J. Pharm. Edu. Res

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Tuberculosis is a pathogenic infection that has created trepidation around the globe due to its repercussion on the health of patients. The iron transport mechanism in mycobacterium plays a pivotal role in bacterial survival; whilst this can be considered an emerging drug target. Salicylate synthase is a member of the MST family and this enzyme is distrait in mammals. It is the first enzyme for the synthesis of mycobactin (siderophores) which is a determinant for iron transport. The present all-embracing review provides overall coverage of the biological and structural outlook of the enzyme salicylate synthase and its inhibitors reported in recent years. Furthermore, this review sheds limelight on the development of novel and more potent salicylate synthase inhibitors.

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Correction of diffusion calculations when using two types of non-rectangular simulation boxes in molecular simulations

Cao

et al. 2019

J Mol Model

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Integration of ligand and structure based approaches for identification of novel MbtI inhibitors in Mycobacterium tuberculosis and molecular dynamics simulation studies

Cited by 5 publications

References 28 publications

Identification of CDK7 Inhibitors from Natural Sources Using Pharmacoinformatics and Molecular Dynamics Simulations

Identification of CDK7 Inhibitors from Natural Sources Using Pharmacoinformatics and Molecular Dynamics Simulations

Molecular Insights into Salicylate Synthase: From Medicinal Chemistry Perspective

Correction of diffusion calculations when using two types of non-rectangular simulation boxes in molecular simulations

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