Sharif Digital Repository

Acidity values of some compound (e.g., alkanes, alcohols, carboxylic acids and amines) with or without boron substitute have been studied theoretically to evaluate the influence of boron on acidity of organic functional groups. We have derived the unoccupied reactive orbital that show the maximum localization on the boron pπ atomic orbital overlapping with the lone-pair orbital of an electron donor. Localization of unoccupied reactive orbital on the boron pπ atomic and the polarizability of the boron center are two factors which affect acidity values of functional groups. Conformational searching was performed using MM (Molecular Mechanics). The most important conformations were optimized at... 

It is believed that intramolecular hydrogen bonding and also conjugation can affect the acidity power of organic molecules. But simultaneous effects of intramolecular hydrogen bonding and conjugation have not investigated systematically yet. In this project, we choose Ascorbic acid as a basic structure. Then we have changed its structure conveniently, and have explored the roles of hydrogen bonding and conjugation on the acidity of this molecule by using B3LYP functional with the 6-311++G(d,p) basis set. After that we similarly investigate these effects on the acidity of three different systems, including enols, enamines and alcohols. In this project we probe the effect of different hydrogen... 

SHP2 has been reported as a critical non-receptor phosphatase enzyme that plays crucial roles in numerous disorders like cancer. The previous studies on this enzyme showed that inhibiting the action of the enzyme comes as a way of controlling enzyme activity. SHP099 was discovered as an Allosteric inhibitor of the enzyme with the most inhibitory effect among all of the studied compounds. In this study we aimed to design novel dipeptide-and sugar-based inhibitors for the allosteric binding site of this enzyme with in-silico studies including docking, molecular dynamic simulation, and free binding energy analysis. Our novel designed drugs possess enough binding properties, low toxicity, and... 

Cyclin-dependent kinases 2 (CDK2) are one of the important proteins in cell cycle regulation and progression. In many human cancer cells, the activity of CDK2 kinases and their related subunits are deregulated, leading to tumor formation. Therefore, inhibition of this enzyme as an attractive therapeutic target can cause cancer cell death in glioblastoma and diffuse large B-cell lymphoma. Using new pharmaceutical structures based on sugar and amino acids is a new approach due to its greater efficacy and fewer side effects than old drugs. In this research, according to the structure of Flavopiridol as one of the CDK2 inhibitors, the active site of CDK2, and the structure of ATP molecule, 50... 

Vimseltinib, a small molecule inhibitor, represents a promising avenue for combating cancers linked to macrophage-associated processes through its targeted action on the CSF1R tyrosine kinase receptor. CSF1R, a pivotal member of the tyrosine kinase receptor family, plays a crucial role in macrophage differentiation and function. This protein's significance is underscored in conditions such as tenosynovial giant cell tumors (TGCTs) and the presence of tumor-associated macrophages, wherein overproduction of CSF1 by neoplastic cells recruits CSF1R-dependent immune cells, fostering tumor expansion. The intricate interplay extends to tumor-associated macrophages, particularly the M2 subtype,... 

This project aims to design a novel structure that can inhibit the activitvation of the c-Met enzyme using amino acids and sugars building blocks. The c-Met enzyme is a receptor tyrosine kinase that plays a significant role in several biological activities such as cell proliferation, survival, and invasion. Abnormal activity of the enzyme is linked to the progression of various types of cancer, including breast, lung, liver, and stomach cancer. The proposed sugar amino acid conjugate structures is expected to increase stability amino acids and dipeptides in the physiological environment, improve membrane permeability via active transport mechanism, and reduce toxicity and side effects by... 

Measuring the binding affinity of a ligand for its target protein is regarded as a critical step in drug design and discovery, owing to its direct correlation with therapeutic efficacy. Conventional molecular docking methods, despite their widespread use in predicting binding affinity, often incur substantial computational and temporal costs, depending on the size and complexity of the protein and the small molecule. Consequently, recent studies have concentrated on employing machine learning and deep learning algorithms to predict both binding sites and affinities. The epidermal growth factor receptor (EGFR), a principal therapeutic target in various cancers, plays a pivotal role in the... 

Many of the significant reactions in chemistry and biology are related to bimolecular nucleophilic substitution (SN2) reactions which have been studied first by Hughes and Ingold in the 1930s. Afterward, many organic chemists have continued this work. Up to now, numerous experimental kinetic and theoretical researches have studied the mechanism of these reactions. Since most SN2 reactions occur in solution, a large number of these studies have been devoted to the solvent effects. One of these effects that has been examined extremely is H-bonding via protic solvents that lowers the energy of an anionic nucleophile relative to the transition state, in which the charge is more diffuse, and... 

N, N′, N″-triethylenethiophosphoramide (Thiotepa) and its oxo analogue (Tepa) as the major metabolite are trifunctional alkylating agents with a broad spectrum of antitumor activity. In vivo and vitro studies show alkylation of DNA by Thiotepa and Tepa can follow two pathways, but it remains unclear which pathway represents the precise mechanism of action. In pathway 1, these agents are capable of forming cross-links with DNA molecules which can be carried out via two different mechanisms. In the first mechanism, the ring opening reaction is initiated by protonating the aziridine, which then becomes the primary target of nucleophilic attack by the N7-Guanine of DNA. The second one is the... 

Since we are exposed to many air pollutants such as different gases daily, this project has attempted to investigate how these gases affect nucleobases, which are the main constituent of the DNA chain. The gases used in this study are sulfur dioxide (SO2), carbon monoxide (CO) and nitric oxide (NO). Each of these gases was studied separately along with the most stable nucleobase in the neutral, anionic and cationic states. The AT and GC base pairs were also exposed to each of these gases and changes (for exampl, the acidity, proton affinity) created in the AT and GC base pairs were examined.The most important properties studied during this project include gas-nucleobase interactions, proton... 

Present work focuses on the influence of Heteroatom(s) on the bacisity of specific group of amines through the intramolecular hydrogen bonding. This group includes Aza-Crown Ethers specifically. We used Spartan and Gaussian packages to gain optimized structures for all compounds in order to explore the influence of the intramolecular hydrogen bonding on the bacisity of amines. All the gas phase optimizations and energy calculations were performed at the DFT/B3LYP/6-311++G(d,p) level of theory. The Hf/6-31+G(d,p) level was used for all single point calculations in the solution phase. As commonly used solvents in organic and biological reactions, the solution phase calculations were carried... 

Nowadays, there is no doubt about the importance of investigation of physicochemical properties of nucleosides in order to determine the structure of these biopolymers. Nucleotides have a variety of roles in cellular metabolism. They are the constituents of nucleic acids: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), the molecular repositories of genetic information. The metal ions play a significant role in several biological processes. Synthesis, replication, and cleavage of DNA and RNA as well as their structure integrity are affected by the presence of these ionized metals in the cell nucleus. To understand the role of cations in the biophysics of DNA, it is necessary first to... 

This project aims to design a drug to fight leukemia and some autoimmune diseases having few side effects. These drugs are composed of natural sugar and amino acid structures. Among the various treatments available, drug structures as inhibitors of enzymes involved in cancer-related cellular processes is an important treatment. Methotrexate is one of the most widely used anticancer drugs in the last half-century and treats leukemia and many autoimmune diseases such as psoriasis. It is a derivative of folic acid (vitamin B9) and one of the drugs with specific properties. It is an anti-folate whose anti-metabolic effects can help kill cancer cells. One of the problems with using this drug to... 

The aim of this study is to devise innovative compounds that impede the function of CK2α enzyme by incorporating amino acids and sugars into their molecular structure. CK2α, a catalytic subunit of CK2 enzyme, operates autonomously and is the only continuously active kinase that does not require an upstream regulator. Emerging evidence highlights CK2α's crucial role in various cancers and infectious diseases, including Covid-19, indicating that suppressing its function could provide a promising approach to improve patient outcomes. To accomplish this objective, the drug design process must take into account both pharmacokinetic and pharmacodynamic properties. Pharmacokinetics, encompassing... 

The enzyme Bruton's tyrosine kinase (BTK) is one of the essential proteins that plays a vital role in the proliferation of B lymphocyte cells. Therefore, it is considered a primary target for restricting the growth of corresponding cancer cells. The side effects of BTK inhibitors, as commonly available drugs, have always been a considerable concern, and efforts to find a more effective drug with fewer side effects have never been rare. Among them, drugs with selectively chosen structures from nature are promising to improve these side effects and achieve greater acceptance through the body's natural system. To address this, innovative drug design methods were employed using various tools,... 

Protein activities are modulated by Kinases through phosphate group transfers, regulating cellular functions. Mutations in kinases are related to cancer initiation, progression, and recurrence. Kinase inhibitors such as Crizotinib have demonstrated efficacy against specific cancers, but limitations and adverse effects necessitate the invention and discovery of novel and potent inhibitors. This study employs Computer-Aided Drug Design techniques to develop natural-based structures targeting the ROS1 Kinase Domain. Molecular fingerprints, Molecular Dynamics Simulations, Docking, and Quantum Calculations are utilized for virtual screening and structure evaluations. A compound library is... 

Hydrogen bond is a type of molecular bonds which occurs between hydrogen and a highly electronegative atom( usually F, N and O) and results to special properties. Polyols and multihydroxyl compounds are among substances which have special properties such as acidity due to the existence of hydrogen bond in their molecular structure. Acidity in these compounds is a result of having stable anions due to intramolecular hydrogen bands. The existence of an electronegative group in addition to hydroxyl groups leads to increase the acidity in these substances. In this project acidities of some polyols and multihydroxyl compounds were calculated in both gas phase and solution phase( DMSO,... 

Blockchain technology, which is known as a technology in the financial sector, has many benefits for non-financial industries and supply chains. Two of the main advantages of blockchain are smart contracts and decentralized decision-making. These two features can effectively achieve the goals of Industry 4.0. Furthermore, this technology increases transparency, resulting in increased efficiency in supply chains, reduced operational costs, and increased control and supervision. In this study, the problem of production-distribution planning in cloud architecture is examined as an example of a cloud supply chain problem, and a blockchain-based architecture is proposed for service composition in... 

Quantum calculation based on the density functional theory (DFT) level and 6-311++G (d,p) basis set was employed to study the relation between the structure and radical scavenging activity of a series of hydroxybenzohydroxamic acid derivatives, namely: [HU]; hyroxyurea, [TX]; 3,4,5-trihydroxybenzamidoxime, [DX]; 3,4-dihydroxybenzohydroxamic acid, [4-HBA]; 4-hydroxybenzohydroxamic acid, [2,3-DHBA]; 2,3-Dihydroxybenzohydroxamic acid, [3,5-DHBA]; 3,5-Dihydroxybenzohydroxamic acid and [2-HBA]; 2-hydroxybenzohydroxamic acid in the gas phase, water and benzene environments. The hydrogen bond property of the studied structures and their radicals as well as radical cations was investigated using... 

This thesis is divided into two parts: In part I, which is theoretical part, we were looking for a computational method which is extensively comparable with experimental results to determine pKa of wide variety of organic compounds. The pKa is an important property in many sciences such as chemistry, biology, and material science, since inclination of a compound to donate or accept a proton is fundamental to understanding many chemical and biochemical processes. Experimentally determined pKa values are not always available from literature sources and often estimated values are employed in their place. It is useful, therefore, to have reliable and accurate means of calculating relative and/or...