Computational screening of some newer potential anti-sickling compounds using docking, ADMET, DFT, and molecular dynamics approaches

Sickle Cell Disease is one of the hemoglobinopathy major pathology behind is vaso -occlusion of RBCs contributing severe complications which has global distribution worldwide. Existing approved drugs available does not promise curative treatment only provides symptomatic relief and repeated intake of medications life-long for healthy survival and periodical blood transfusions doesn’t eradicate the sufferings of individuals, only tedious genetic stem cell transplants are to combat the disease. There is need to discover novel potent anti-sickling agent which inhibits RBCs polymerization and have better anti-oxidant properties. So, two promising hybrid molecules having reported anti-oxidant activity and inhibiting polymerisation of RBCs is the choice for moiety i.e. one is of Phthalimide and other moiety is Caffeic acid from them some newer analogues were developed to discover more effective and less toxic Compounds an anti- sickling agent. The Objective of this work was to discover newer better anti-sickling candidates through Computational approach. Best novel analogues of Phthalimide Pharmacophore and Caffeic acid Pharmacophore was formed using bio-isosteric design method and total of 373 analogues were created, each focusing on to get improved Pharmacokinetic Properties and less toxic analogues by using ADMET 3.0 Software and Orisis Software. Molecular docking studies were conducted using Auto Dock Vina Pyrex software followed by ICM pro bowser for visualizing interactions of Protein and Ligand. To analyse stability of compound, Molecular dynamic simulation studies were done using Desmond Schrodinger suite Software. DFT analysis of analogues were done to analysis an electronic stability. The best docking scores of analogues were obtained with better Pharmacokinetic profile, good medicinal properties and low toxicity levels from respective Pharmacophores i.e. P-2 with − 10.4 Kcal/mol and C-2 with − 9.0 Kcal/mol against protein 2HBS. Molecular dynamic Simulation of P-2 and C-2 was conducted, reveals that the complexes-maintained stability through 100ns. DFT calculations was also predicted for the stability and electronic properties of analogues P-2 and C-2 both molecules exhibited distinct conformational stability and unique electronic responses, offering deep insight into their reactivity and molecular functionality. Computational approach combining Molecular docking, Molecular dynamic simulation and toxicity promise discovery of better candidates for development of potential anti- sickling agents. In this study Some best Novel analogues with better Pharmacokinetic Properties and least toxicity of Pharmacophores were identified by using Computational approaches to treat genetic acquired haematological disorder i.e. Sickle cell disease. As from the Present Research work better results were achieved than already existing approved drug for treatment of this disease and it is validated through Molecular Docking studies, ADMET Studies, DFT Studies and Molecular Dynamic Studies.