Crystal structure determination and computational studies of 1,4-dihydropyridine derivatives as selective T-type calcium channel blockers

Different types of calcium channels are crucial regulators of many key physiological functions throughout the body. Therefore, calcium channel modulators are accepted as precious molecules for the therapeutic intervention of various pathologies ranging from cardiovascular to neurological diseases. 1,4-dihydropyridines (DHPs) primarily target L-type calcium channel (Ca(v)1.2) for the treatment of hypertension and occupy a central position among all calcium channel blockers. Subsequently, T-type calcium channel Ca(v)3.2 isoform has been established to play a significant role in chronic pain conditions. Despite the growing interest and identification of many compounds with Ca(v)3.2 blocking activities, no molecule has passed the clinical trials and approved for the treatment of pain by now. Our group has recently identified two DHP-based molecules (HM8 and MD20) that selectively blocked T-type over L-type calcium channel. As these compounds hold great therapeutic value as potential drug candidates, we carried out further structural and computational analyses to gain insights into their various properties. Initially, the three-dimensional structure of HM8 was resolved by single-crystal X-ray analysis. The computational analysis encompassed density functional theory (DFT) and molecular dynamics (MD) simulations. DFT calculations were used to identify local reactivity properties and pharmaceutical stability, while time-dependent DFT calculations were used to simulate the UV/Vis spectra and identify the molecular parts principally responsible for the light absorption. MD simulations were used to understand the influence of water on studied molecules, and also to identify the substances that could be potentially used as excipients in pharmaceutical formulations based on HM8 and MD20. (C) 2021 Elsevier B.V. All rights reserved

Investigation of reactive properties, adsorption on fullerene, DFT, molecular dynamics simulation of an anthracene derivative targeting dihydrofolate reductase and human dUTPase

Anthracenes are aromatic compounds with flexible structure and reactivity which are of great interest to theoretical and experimental chemists. Theoretical investigations of 1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione (Mitoxantrone) (DDEA) based on density functional theory, molecular dynamics and adsorption on fullerene are reported in the present research. The suitable situation for adsorption with fullerene (C60) is the cyclohex-2-ene-1,4-dione ring of DDEA. Selected quantum-molecular descriptors have been calculated to predict the most reactive sites of the DDEA molecule. Interactions of DDEA with water have been studied using MD simulations. MD simulations were also used to study solubility parameter, a significant quantity for the development of pharmaceutical formulations. The affinity of DDEA on human dihydrofolate reductase and deoxyuridine triphosphatase enzymes was investigated by MD simulation of the protein-ligand complex obtained by molecular docking study. Communicated by Ramaswamy H. Sarm

Molecular structure, chemical reactivity and molecular docking studies of 1,7,8,9-tetrachloro-10,10-dimethoxy-4-[3-(4-benzylpiperazine-1-yl)propyl]-4-azatricyclo[5.2.1.02,6] dec-8-ene-3, 5-dione

1,7,8,9-tetrachloro-10,10-dimethoxy-4-[3-(4-benzylpiperazine-1-yl)propyl]-4-azatricyclo[5.2.1.02,6] dec-8-ene-3, 5-dione (TCDBPAD) have been calculated theoretically to obtain optimized geometry, vibrational frequencies and corresponding vibrational assignments. Charge transfer within the molecule was evaluated using HOMO and LUMO analysis. By hyper-conjugative interaction and charge delocalisation which can be analysed using NBO analysis, we can understand about the stability of the molecule. By using DFT method Molecular electrostatic potential (MEP) was calculated. First hyperpolarizability values are calculated in order to check the non-linear optical activity. Using MD simulations, we have visualized the ALIE and Fukui functions. The degradation property of compound in presence of water was evaluated using RDF curves. By solubility parameter we have identified suitable excipient for the title compound. Molecular docking studies proved that the title compound can be used for the treatment of Cardiovascular and Cerebrovascular diseases

Spectroscopic investigations, DFT calculations, molecular docking and MD simulations of 3-[(4-Carboxyphenyl) carbamoyl]-4-hydroxy-2-oxo-1, 2-dihydroxy quinoline-6-carboxylic acid.

By FT-IR, FT-Raman and DFT computations spectral characterization of 3-[(4-Carboxyphenyl) carbamoyl]-4-hydroxy-2-oxo-1, 2-dihydroxy quinoline-6-carboxylic acid was performed. Computational calculations were done using B3LYP/6-31G(d’) basis set. Vibrational assignments of wavenumbers were performed on the basis of potential energy distribution. Donor acceptor interactions were evaluated using NBO analysis. To foresee the important reactive sites of the title compound we combined DFT calculations and molecular dynamics (MD) and visualized the ALIE and Fukui functions. Sensitive nature of the compound towards autoxidation and degradation in the presence of water was investigated by the calculation of BDE and RDF. By molecular docking the compound forms a stable complex with ubiquinol-cytochrome–c reductase inhibitor