Pharmacophore based virtual screening, molecular docking and molecular dynamic simulation studies for finding ROS1 kinase inhibitors as potential drug molecules

Vanajothi, Ramar; Vedagiri, Hemamalini; Al-Ansari, Mysoon M.; Al-Humaid, Latifah; Premkumar, Kumpati

doi:10.1080/07391102.2020.1847195

Cited by 10 publications

(7 citation statements)

References 45 publications

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“…The flavonoids were further escalated for molecular dynamics simulations to observe their behavior at physiological conditions and also to gain insight into the key residues required for selective ROS-1 inhibition. The representative structures for the 10 flavonoids were extracted from the stable MD trajectories ( Figure 3 ) and the obtained flavonoids exhibited interactions with the residues of the WT and MT ROS-1 kinase as seen in previous studies [ 45 , 47 ]. Additionally, the flavonoids demonstrated no Arg2032-induced steric clashes and instead formed interactions with the residue via hydrophobic and van der Waals bonds ( Figures S2 and S3 ).…”

Section: Discussionmentioning

confidence: 99%

“…Encouraged from the above-mentioned efforts, we designed a pharmacophore-based virtual screening strategy [ 30 , 35 , 42 , 43 , 44 , 45 , 46 ] combined with molecular docking and molecular dynamics simulations to acquire flavonoids as effective WT and MT ROS-1 RTK inhibitors. Accordingly, a receptor-ligand pharmacophore model was developed deriving HBA, HBD and Hy as key pharmacophoric features ( Figure 1 ).…”

Section: Discussionmentioning

confidence: 99%

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Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics

et al. 2021

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Non-small cell lung cancer (NSCLC) is a lethal non-immunogenic malignancy and proto-oncogene ROS-1 tyrosine kinase is one of its clinically relevant oncogenic markers. The ROS-1 inhibitor, crizotinib, demonstrated resistance due to the Gly2032Arg mutation. To curtail this resistance, researchers developed lorlatinib against the mutated kinase. In the present study, a receptor-ligand pharmacophore model exploiting the key features of lorlatinib binding with ROS-1 was exploited to identify inhibitors against the wild-type (WT) and the mutant (MT) kinase domain. The developed model was utilized to virtually screen the TimTec flavonoids database and the retrieved drug-like hits were subjected for docking with the WT and MT ROS-1 kinase. A total of 10 flavonoids displayed higher docking scores than lorlatinib. Subsequent molecular dynamics simulations of the acquired flavonoids with WT and MT ROS-1 revealed no steric clashes with the Arg2032 (MT ROS-1). The binding free energy calculations computed via molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) demonstrated one flavonoid (Hit) with better energy than lorlatinib in binding with WT and MT ROS-1. The Hit compound was observed to bind in the ROS-1 selectivity pocket comprised of residues from the β-3 sheet and DFG-motif. The identified Hit from this investigation could act as a potent WT and MT ROS-1 inhibitor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics

et al. 2021

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“…Pro le score above zero in the Verify 3D graph [39,40] corresponds to the acceptable environment of the model. The ProSA [41] results in nding the potential error on the predicted model revealed the Z-score values of -4.56 against the template which indicates that protein structure is well correlated with the crystal structure of similar length and within the acceptable range.…”

Section: Structure Evaluationmentioning

confidence: 96%

Identification of Novel Chemical Entities for Mirk/Dyrk1B Receptor Using Molecular Modeling and Molecular Dynamic Approaches

Vanajothi

Bhavaniramya

Umadevi

et al. 2021

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Cancer is a major health problem worldwide and one of the leading death-causing diseases. Mirk (Minibrain-related kinase is a member of the dual-specificity tyrosine-phosphorylation-regulated kinase (Dyrk) family that is highly upregulated in various solid tumors and mediates cell survival including lung cancer. Mirk effectively increases the expression of a series of antioxidant genes, which scavenge the reactive oxygen species and stabilize the p27kip1 that maintain the viability of the quiescent cancer cell and also mediates the cell cycle and survival of cancer cells by influencing the MAPK/ERK signaling pathway. Hence, Mirk acts as a novel therapeutic target for cancer prevention. Owing to the unavailability of the three-dimensional structure of Mirk, in the present study, we have modeled the 3D structure of Mirk, based on the crystal structure of Dyrk1a as a template, and subsequently used it as a target for virtual screening and molecular docking against a small molecule database. Based on the visual inspection, four best hits such as Chembridge_ID 7768949, 7771055, 7758866, and 7764195 have high binding affinity, good docking score, and pharmacokinetic properties were shortlisted. Further, the dynamic stability of lead molecules with modeled Mirk/Dyrk1B was evaluated using 10 ns molecular dynamics simulation approach. The four hit molecules exhibited good and stable binding complex in the binding pocket of the target protein. Collectively the finding of this study suggested that the identified molecules may serve as potential effective anti-cancer inhibitors for cancer prevention.

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“…Lorlatinib (Lorbrena) and cabozantinib (Cometriq) are the inhibitors currently being studied to overcome crizotinib resistance [190,191]. Lorlatinib revealed a strong antitumor activity also in the presence of other ROS1 point mutations including L2026M, D2033N, and S1986, known to induce the development of crizotinib-resistance [192].…”

Section: Proto-oncogene Tyrosine-protein Kinase Rosmentioning

confidence: 99%

Clinical Relevance of Targeted Therapy and Immune-Checkpoint Inhibition in Lung Cancer

et al. 2023

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Lung cancer (LC) represents the second most diagnosed tumor and the malignancy with the highest mortality rate. In recent years, tremendous progress has been made in the treatment of this tumor thanks to the discovery, testing, and clinical approval of novel therapeutic approaches. Firstly, targeted therapies aimed at inhibiting specific mutated tyrosine kinases or downstream factors were approved in clinical practice. Secondly, immunotherapy inducing the reactivation of the immune system to efficiently eliminate LC cells has been approved. This review describes in depth both current and ongoing clinical studies, which allowed the approval of targeted therapies and immune-checkpoint inhibitors as standard of care for LC. Moreover, the present advantages and pitfalls of new therapeutic approaches will be discussed. Finally, the acquired importance of human microbiota as a novel source of LC biomarkers, as well as therapeutic targets to improve the efficacy of available therapies, was analyzed. Therapy against LC is increasingly becoming holistic, taking into consideration not only the genetic landscape of the tumor, but also the immune background and other individual variables, such as patient-specific gut microbial composition. On these bases, in the future, the research milestones reached will allow clinicians to treat LC patients with tailored approaches.

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Pharmacophore based virtual screening, molecular docking and molecular dynamic simulation studies for finding ROS1 kinase inhibitors as potential drug molecules

Cited by 10 publications

References 45 publications

Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics

Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics

Identification of Novel Chemical Entities for Mirk/Dyrk1B Receptor Using Molecular Modeling and Molecular Dynamic Approaches

Clinical Relevance of Targeted Therapy and Immune-Checkpoint Inhibition in Lung Cancer

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