Parkinson's disease is an illness that involves the progressive deterioration of the nervous system. It was considered a loss of axonal projections of dopamine neurons in the substantia naigra neuronal cytoplasmic aggregate of Alpha syn and Ubiquitin, indicating this disease's existence ¹. A recent study suggests that mitochondrial dysfunction is a course of Parkinson's disease. Heterocyclic compounds have medicinal properties and considering the various pharmacophore groups and rings responsible for biological activity, they can be selected from an existing chemical database for in-silico testing and prediction of biological activity based on the docking scores. Mitochondrial regulation, reactive oxygen species, neuronal damage, and intracellular calcium homeostasis are the possible mechanisms of the formation of Parkinson's disease. Controlling the reactive calcium through “voltage-gated calcium channels” is one of the methods to prevent Parkinson's disease. The “L-type calcium channels” are targeted for drug development of Parkinson's disease. The activation of L-type voltage channels penetrates holes on the surface of the plasma membrane. The deactivation of L-type channels is a strategy for controlling Parkinson's disease and Alzheimer’s disease. The heterocyclic compound that modulates calcium channels is a promising candidate for lead compounds for drug development. Calcium channel drugs have been used extensively for cardiovascular diseases. The chemical classes of drugs used for Calcium channel blocking activity for cardiovascular disorders are 1 4 dihydropyridines, phenyl alkyl amines, and benzodiazepines. They bind to different calcium channels. The dihydropyridines and phenyl alkyl amines bind CavAb ².

The receptor 5KMH is classified as a transporter protein. It is a complex of CavAb and verapamil with four chains ABCD of voltage-gated cation and sodium family, voltage-depended on channel Super family and ion transport domain with Alpha helical structure ³. It is a Calcium Ion selective protein created by mutation of the NaVAb channel. Dihydropyridines and phenyl alkaylamines inhibit these. The phenyl alkaylamines for the Br Verapamil bind to the combined cavity of protein receptors, blocking the Ion conducting pathway. The heterocyclic compound selection was based on structure similarity mode with compounds of similar rings like phenyl alkaylamines and dihydropyridines ⁴.

The compounds selected are. “Diethyl 2, 6-dimethyl-4-(3-nitrophenyl) - 1, 4-dihydropyridine-3, 5-dicarboxylate” of PubChem id 282663 ⁵, “[6], 4’- Hydroxy-3'- methoxide acetophenone", (acetovanilone) of PubChem id 2214 is an aromatic ketone used as anti-inflammatory anti-rheumatic ⁶. “Diethyl 2,6-dimethyl-4-(4-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylate”, with a hydrogen bond donor count one, and PubChem id 210905 ⁷, "2,(3,4-methoxyphenyl)- 5-[2-(3,4-methoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile" (VERAPAMIL) with a PubChem id 2520 is an approved calcium channel blocker standard drug 8 “[(3R,4S)- 1-[2-(dimethylamine)ethyl]-4-(4-methoxyphenyl)-7-methylsulfanyl-2-oxo-4,5-dihydro-3H-1-benzazepin-3-yl]” acetic acid with a PubChem id 14156293 with a hydrogen bond donor count 0 9 “2-(3,4-methoxyphenyl)- 5-(2,2-phenylethylamine)- 2-propan-2-ylpentanenitrile” with a PubChem id -10719948 with hydrogen bond donor count one and acceptor count 4 ¹⁰.

Computational techniques such as auto dock 4.2.7 and PyRX docking software were used for this in-silico study. The docking scores were calculated and compared. This comparison of the two complementary values will substantiate the accuracy of this study. The ADMET parameters were predicted using pkCSM.

“Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures” tool. The aforementioned computational tools predicted ant-Parkinsonism activity and their drug penetration to biological cavities for desired biological activity with a comparative result. The standard used to compare the docking scores of selected heterocyclic compounds was a well-established calcium channel blocker and anti-hypertensive drug, verapamil. The protein target used for this study was CavAb (PDBID 5KMH) in complex with Br Verapamil ¹¹. The protein receptor was downloaded from RCSB PDB, and the ligands were selected based on a structure similarity with Phenylalkylamines and dihydropyridines. They were downloaded from the Pub chem database after citations. The files were saved in a separate folder containing Biovia Discovery Studio and auto dock tools. Biovia Discovery Studio visualizer cleaned and visualized the ligands and target.

Table 1: ADMET parameters of high-scoring compound 2-(3,4-dimethoxyphenyl)-5-(2,2-diphenylethylamino)-2-propan-2-ylpentanenitrile

The present study revealed that among the five heterocyclic compounds selected for the study, (2-(3, 4-methoxyphenyl)-5-(2, 2-phenylethylamine)-2-propan-2-ylpentanenitrileexhibited minimum binding energy which indicated a good predicted biological activity [Table 1]. The binding energies were calculated as -6.25 (Auto dock) and - 9.5 (PyRX). The values are complementary, and the difference exists due to the exhaustiveness parameter, the grid parameters, and the difference in force fields. The next compound of interest found is [(3R, 4S)-1-[2-(dimethyl amino) ethyl]-4-(4-methoxyphenyl)-7-methylsulfanyl-2-oxo-4, 5-dihydro-3H-1-benzazepin-3-yl] acetate. Binding energy -5.37 and -7.9 for auto dock and PyRX, respectively. PyRX always showed a high negative value for binding energy. The compound of choice that gave a good score can be considered as a lead compound for anti-parkinsonism drug development. It may inhibit the voltage-gated L-type calcium ion channels, decreasing calcium ion entry to cells and reducing neurons' hyper excitability.

Table 2: ADMET parameters of high-scoring compound 2-(3,4-methoxyphenyl)-5-(2,2-phenylethylamine) -2-propane-2-ylpentanenitrile