A correlative approach in 3D structures of potential Alzheimer disease inhibitors

Ravindranath, Kannika Byadarahalli; Kandaswamy, Saravanan; Sheshadri, S. N.; Al-Odayni, Abdel-Basit; Saeed, Waseem Sharaf; Alzubaidy, Nabil Najib; Manjunath, N K; Manju, N.; Gowda, Javare; Shankar, Madan Kumar

doi:10.1016/j.molstruc.2023.135684

Cited by 1 publication

(3 citation statements)

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“…This is exactly correlating with the binding energy obtained from MD analysis. However, this total electrostatic energy is found to be lower than the recently reported JNK3 and ACE2 complexes as well as higher than the SARS Cov-19 Mpro, HER2 complexes. , Therefore, the electrostatic interaction energy calculation is also an additional support to evaluate the strength of noncovalent interactions.…”

Section: Resultsmentioning

confidence: 63%

“…The NCI isosurface map was generated for noncovalent interactions obtained in both crystal and protein environments (Figures and S5) which shows the NCI isosurface between two interacting atoms that confirms the strength of the interaction. Furthermore, studies showed the electrostatic interaction energy also plays a vital role in the analysis of stability and strength of intermolecular interactions in the protein environment. ,, The calculated total electrostatic interaction energy of the CDC7 kinase–PYRA-2 complex (−58.08 kcal/mol) carries higher energy than that of the CDC7 kinase–PYRA-1 complex (−40.03 kcal/mol). This is exactly correlating with the binding energy obtained from MD analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The surface coverage ranging from red to blue between the internal d i and external d e surfaces was employed to construct Hirshfeld surfaces with a normalized contact distance ( d norm ). The shapes of fingerprint plots were used to describe the various intermolecular interactions of the molecules in the crystal as well as to assist in quantifying the contact distances to Hirshfeld surface analysis ( d i , d e ), which revealed the range from 0.6 to 2.8 considering reciprocal contacts. − In order to comprehend the predicted structure–property relationships of the synthesized molecules, intermolecular interaction energies were determined at the B3LYP/6-31G(d,p) level of theory and categorized into electrostatic ( E elec ), polarization ( E pol ), dispersion ( E disp ), and repulsion ( E rep ) energy components. ,, …”

Section: Methodsmentioning

confidence: 99%

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A Structural and In Silico Investigation of Potential CDC7 Kinase Enzyme Inhibitors

Mookkan,

Kandasamy,

Al-Odayni

et al. 2023

ACS Omega

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A crucial role in the regulation of DNA replication is played by the highly conserved CDC kinase. The CDC7 kinase could serve as a target for therapeutic intervention in cancer. The primary heterocyclic substance is pyrazole, and its derivatives offer great potential as treatments for cancer cell lines. Here, we synthesized the two pyrazole derivatives: 4-(2-(4-chlorophenyl)hydrazinyl)-5-methyl-2-tosyl-1H-pyrazol-3(2H)-one (PYRA-1) and 4-(2-(2,4-difluorophenyl)hydrazinyl)-5-methyl-2-tosyl-1H-pyrazol-3(2H)-one (PYRA-2). The structural confirmation of both the compounds at the three-dimensional level is characterized using single crystal X-ray diffraction and density functional theory. Furthermore, the in silico chemical biological properties were derived using molecular docking and molecular dynamics (MD) simulations. PYRA-1 and PYRA-2 crystallize in the P-1 ( a = 8.184(9), b = 14.251(13), c = 15.601(15), α = 91.57(8), β = 97.48(9), 92.67(9), V = 1801.1(3) 3, and Z = 2) and P2 1 / n ( a = 14.8648(8), b = 8.5998(4), c = 15.5586(8), β = 116.47(7), V = 1780.4(19) 3, and Z = 4), space groups, respectively. In both PYRA-1 and PYRA-2 compounds, C–H···O intermolecular connections are common to stabilize the crystal structure. In addition, short intermolecular interactions stabilizes with C–H···π and π–π stacking. Crystal packing analysis was quantified using Hirshfeld surface analysis resulting in C···H, O···H, and H···H contacts in PYRA-1 exhibiting more contribution than in PYRA-2. The conformational stabilities of the molecules are same in the gas and liquid phases (water and DMSO). The docking scores measured for PYRA-1 and PYRA-2 with CDC7 kinase complexes are −5.421 and −5.884 kcal/mol, respectively. The MD simulations show that PYRA-2 is a more potential inhibitor than PYRA-1 against CDC7 kinase.

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Section: Resultsmentioning

confidence: 63%