Computational Modelling Strategies for Exploring Triazolopyridazine PIM1 Kinase Inhibitors as Anticancer Agents


Дәйексөз келтіру

Толық мәтін

Аннотация

Background:PIM (Proviral Integration site for Moloney Murine Leukemia virus) kinases are members of the class of kinase family serine/threonine kinases, which play a crucial role in cancer development. As there is no drug in the market against PIM-1, kinase has transpired as a budding and captivating target for discovering new anticancer agents targeting PIM-1 kinase.

Aim:The current research pondered the development of new PIM-1 kinase inhibitors by applying a ligand-based and structure-based drug discovery approach involving 3D QSAR, molecular docking, and dynamics simulation.

Methods:In this study, association allying the structural properties and biological activity was undertaken using 3DQSAR analysis. The 3D-QSAR model was generated with the help of 35 compounds from which the best model manifested an appreciated cross-validation coefficient (q2) of 0.8866 and conventional correlation coefficient (r2) of 0.9298, respectively and the predicted correlation coefficient (r2 pred) was obtained as 0.7878.

Results:The molecular docking analysis demonstrated that the analogs under analysis occupied the active site of the PIM-1 kinase receptor and interactions with Lys67 in the catalytic region, Asp186 in the DFG motif, and Glu171 were noticed with numerous compounds.

Discussion:Furthermore, the molecular dynamics simulation study stated that the ligand portrayed strong conformational stability within the active site of PIM-1 kinase protein, forming two hydrogen bonds until 100 ns, respectively.

Conclusion:Overall outcomes of the study revealed that applications of the ligand-based drug discovery approach and structure-based drug discovery strategy conceivably applied to discovering new PIM-1 kinase inhibitors as anticancer agents.

Авторлар туралы

Vinayak Walhekar

Department of Pharmaceutical Chemistry,, BVDU’S Poona College of Pharmacy

Email: info@benthamscience.net

Chandrakant Bagul

Department of Pharmaceutical Chemistry, BVDU’S Poona College of Pharmacy,

Email: info@benthamscience.net

Dileep Kumar

Department of Pharmaceutical Chemistry,, BVDU’S Poona College of Pharmacy

Email: info@benthamscience.net

Garlapati Achaiah

University College of Pharmaceutical Sciences, Kakatiya University

Email: info@benthamscience.net

Amol Muthal

Department of Pharmacology,, BVDU’S Poona College of Pharmacy

Email: info@benthamscience.net

Ravindra Kulkarni

Department of Pharmaceutical Chemistry,, BVDU’S Poona College of Pharmacy

Хат алмасуға жауапты Автор.
Email: info@benthamscience.net

Maccha Basavarju

Department of Pharmaceutical Chemistry,, Jayamukhi Institute of Pharmaceutical Sciences

Email: info@benthamscience.net

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