Molecular dynamics (MD) simulation is an emerging in silico technique with potential applications in diverse areas of pharmacology. Over the past three decades MD has evolved as an area of importance for understanding the atomic basis of complex phenomena such as molecular recognition, protein folding, and the transport of ions and small molecules across membranes. The application of MD simulations in isolation and in conjunction with experimental approaches have provided an increased understanding of protein structure-function relationships and demonstrated promise in drug discovery. AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis. C-Met inhibitor MK-8003 radiosensitizes c-Met-expressing non-small-cell lung cancer cells with radiation-induced c-Met-expression. Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53. C-Met Inhibitor MK-8003 Radiosensitizes c-Met-Expressing Non-Small Cell Lung Cancer Cells with Radiation-Induced c-Met-Expression. In this study we for the first time designed small-molecule PUMA derived peptide mimetic inhibitors for mitigating a potential radiation-induced cell death. These chemical recored scaffolds are consisting of linked small pharmaco-fragments and DNA-induced nucleic acid mimicking molecules that may interact with the DNA double-strand breaks (called Dbait) and would possible in the future act as a disorganizing damage signaling and DNA repair druggable compound. We in silico analyzed the fitness scoring results and the pharmaco-docking free energy binding effects of our synthetic mimotopic Dbait lignads in conserved DNA mutant regions responsible for the tumor growth and performed preliminary ligand structure based QSAR studies of their mechanism(s) of action. Here, in Biogenea we finally in silico multi-molecularly targeted conserved Radiosensitization regions of Human Cancer binding domains by Modulating Inhibitor of apoptosis purpose for the potentiating of a future enhanced DNA repair activity which is often associated with tumor resistance to radiotherapy. Although many radiosensitizers have been developed, their clinical benefit is hampered by a failure to improve the therapeutic ratio due to a lack of tumor specific delivery over normal tissue. We propose to utilize drug conjugated activatable cell penetrating peptides (ACPP) as tumor selective delivery vehicles for the in silico of a fragment ligand based novel multitargeted potent radiosensitizers. Cyclic RGD pretargeted ACPP (ACPP-RGD) are selectively cleaved and activated in the tumor microenvironment through tumor associated matrix metalloproteinase activity and RGD binding integrins utilising Molecular dynamics in silico drug discovery simulations from structure function relationships to a small-molecule PUMA targeted ACPP (ACPP-RGD) peptide mimotopic hyper-Inhibitory ligand pocket binding as a potent pharmacoregulator comprising potential mitigation activities of the radiation-Induced cell death.
Molecular dynamics simulations: structure function relationships; ligand pocket binding; in silico; drug discovery; small-molecule; PUMA targeted; ACPP (ACPP-RGD) peptide; mimotopic; hyper-Inhibitory; potent pharmacoregulator; potential activities; mitigation; radiation-Induced cell death; Molecular dynamics simulations, Cytochrome P450, Drug-drug interactions, Genetic polymorphism, Drug design, Allosteric binding sites, Cryptic binding sites