Small molecules such as metabolites and drugs play essential roles in biological processes and pharmaceutical industry. Knowing their interactions with biomacromolecular targets demands a deep understanding of binding mechanisms. Dozens of papers have suggested that discovering of the binding event by means of conventional unbiased molecular dynamics (MD) simulation urges considerable amount of computational resources, therefore, only one who holds a cluster or a supercomputer can afford such extensive simulations. Thus, many researchers who do not own such resources are reluctant to take the benefits of running unbiased molecular dynamics simulation, in full atomistic details, when studying a ligand binding pathway. Many researchers are impelled to be content with biased molecular dynamics simulations which seek its validation due to its intrinsic preconceived framework. In this work, we have presented a workable stratagem to encourage everyone to perform unbiased (unguided) molecular dynamics simulations, in this case a protein-ligand binding process, by typical desktop computers and so achieve valuable results in nanosecond time scale. Here, we have described a dynamical binding’s process of an anticancer drug, the dasatinib, to the c-Src kinase in full atomistic details for the first time, without applying any biasing force or potential which may lead the drug to artificial interactions with the protein. We have attained multiple independent binding events which occurred in the nano-second timescales, surprisingly as little as ∼30 ns. Both the protonated and deprotonated forms of the dasatinib reached the crystallographic binding mode without having any major intermediate state during induction. Supplementary information Supplementary data are available at Bioinformatics online.

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8Small molecules such as substrates, effectors and drugs play essential roles in biological 9 processes. Knowing their interactions with biomacromolecular targets demands a deep 10 understanding of binding and unbinding mechanisms. Dozens of papers have suggested that 11 discovering of either binding or unbinding events by means of conventional UMD simulation 12 urges a considerable amount of computational resources, therefore, only one who holds a 13 supercomputer can afford such extensive simulations. Capabilities of full atomistic Unbiased 14 Molecular Dynamics (UMD) simulation have been undervalued within the scientific community. 15 Thus, myriads of researchers are impelled to be content with debatable biased MD simulations 16 which seek validation for its preconceived framework. In this work, we present a stratagem to 17 empower everyone to perform UMD simulations of protein-ligand binding and unbinding by 18 typical desktop computers and achieve valuable and high-cost results in nanosecond time scale. 19 Here, we have described kinetics of binding and unbinding of anticancer drug, dasatinib, to c-Src 20 kinase in full atomistic details for the first time. We have attained multiple independent binding 21 and unbinding events occurred in the nano-second timescale, even in times as little as 30 and 22 392.6 ns respectively, without presence of any biasing forces, an achievement that nobody has 23 ever assumed to be possible. 24 Ligand binding and unbinding pathway, Dasatinib, c-Src kinase 26 27 28Small molecule compounds are involved in nearly all cellular mechanisms and studying 29 their roles can unravel secrets behind the scenes. These compounds can trigger cell signaling and 30 metabolic pathways by interacting and binding to certain biomacromolecules like proteins and 31 nucleic acids. Over the last few decades, sophisticated methods such as X-ray crystallography, 32 NMR and electron microscopy revealed numerous structural details of many protein-ligand 33 complexes. However, these complexes are just one or some static poses of a vivid system which 34 its function is completely swayed by its movements and dynamics. Furthermore, in many 35 molecular targets like androgen receptor (PDB ID: 2Q7I) 1 , the binding pocket is buried deep 36 inside the protein structure. The X-ray crystallographic structure doesn't reveal any details about 37 the process of induction and the binding pathway, how the ligand makes an entrance into the 38 protein and how it affects residues on its journey to reach the native binding pose. According to 39 the Food and Drug Administration (FDA), small molecules make up the main proportion of 40 approved drugs on the pharmaceutical market today. Thus, understanding the induction and 41 binding mechanisms of small molecules to their molecular targets can immensely assist 42 researchers to optimize and design much more specific and selective drugs accompanied by 43 extremely low side-effects. Therefore, emergence of a complementary method which can take 44 the advantages of ...

As RAS protein is highly significant in signaling pathways, involving cell growth, differentiation and apoptosis; the Ras GTPase proteins play a significant as a master switch in the appearance of many diseases, including 20-30% of all cancers. So, the K-RasG12V mutant was selected as a drug target in present study. This mutant is involved in gastric cancer, lung and pancreatic carcinoma, and colon cancers. So, we employed the structure-based drug design methods and molecular dynamics simulations to undergo virtual screening on natural products small molecules and predicted some new potent therapeutic inhibitors. Finally, ZINC15671852, ZINC85592862, ZINC85567582 and ZINC03616630 final Hits were identified as potent inhibitors from among more than 79,000 bioactive compounds from natural resource. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-P/GBSA) calculation results have also demonstrated that these molecules obtained higher binding free energy than co-crystalized reference ligand.

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