A Virtual Screening Approach for the Identification of High Affinity Small Molecules Targeting BCR-ABL1 Inhibitors for the Treatment of Chronic Myeloid Leukemia.

CML originates due to reciprocal translocation in Philadelphia chromosome leading to the formation of fusion product BCR-ABL which constitutively activates tyrosine kinase signaling pathways eventually leading to abnormal proliferation of granulocytic cells. As a therapeutic strategy, BCR-ABL inhibitors have been clinically approved which terminates its phosphorylation activity and retards cancer progression. However, a number of patients develop resistance to inhibitors which demand for the discovery of new inhibitors. Given the drawbacks of present inhibitors, by high throughput virtual screening approaches, present study pursues to identify high affinity compounds targeting BCR-ABL1 anticipated to have safer pharmacological profiles. Five established BCR-ABL inhibitors formed the query compounds for identification of structurally similar compounds by Tanimoto coefficient based linear fingerprint search with a threshold of 95% against PubChemdatabase. Assisted by MolDock algorithm all compounds were docked against BCR-ABL protein in order to retrieve high affinity compounds. The parents and similars were further tested for their ADMET propertiesand bioactivity. Rebastinib formed higher affinity inhibitor than rest of the four established compound investigated in the study. Interestingly, Rebastinib similar compound with Pubchem ID: 67254402 was also shown to have highest affinity than other similars including the similars of respective five parents. In terms of ADMET properties Pubchem ID: 67254402 had appreciable ADMET profile and bioactivity. However, Rebastinib still stood as the best inhibitor in terms of binding affinity and ADMET properties than Pubchem ID: 67254402. Nevertheless, owing to the similar pharmacological properties with Rebastinib, Pubchem ID: 67254402 can be expected to form potential BCR-ABL inhibitor.

Helix-Coil Transition Signatures B-Raf V600E Mutation and Virtual Screening for Inhibitors Directed Against Mutant B-Raf.

BACKGROUND: Mutation in the B RAF at V600E has been well implicated in the carcinogenesis that makes it as an attractive therapeutictarget. In the present study, we sought to identify the basis of V600E mutation at functional and structural grounds. The study also endeavors in identification of small molecule as a potential candidate with considerable pharmacological profile than available BRAF inhibitors through computational approaches. METHODS: The functional effects of V600E mutation was predicted using SIFT and Polyphen servers. Protein structural alterations werepredicted using SDM server and RMSD calculations. Virtual screening was performed considering existing BRAF inhibitors viz., Vemurafenib, Sorafenib, Dabrfenib, Trametinibthat formed query compounds for shape similarity search by Tanimoto similarity indices with a threshold of 95%. Compound with high affinity as similar to query compound was retrieved and screened for its ADMET properties. RESULTS: The SNP was shown to be highly vulnerable to malfunction and have damaging effects. Mutated protein showed that the secondary structure was irregular and side chain hydrogen bonds were unsaturated. The superimposition of wild onto mutated V600E BRAF revealed helix-coil transition occurring wherein residues Val 502, Leu 505, Arg506, Lys 507 assumed coiled conformation in the mutated BRAF. Virtual screening led to identification of SCHEMBL298689 akin to Vemurafenib as high affinity B-Raf inhibitors; with least toxicity and optimal bioactivity. CONCLUSION: In the present investigation, we put forth the structural and functional basis of B RAF V600E mutation showing helix coil transitions. In addition identified high affinity compound targeting V600E B RAF through virtual screening.