Selection of semiempirical calculation methods for insecticide development

Acta Pharmaciae Indonesia: Acta Pharm Indo Iswanto et al (2023) Vol 11(1): 7046 https://doi.org/10.20844/1.api.2023.11.1.7046 E-ISSN 2621-4520 Open Access RESEARCH ARTICLE Selection of semi-empirical calculation methods for insecticide development Ponco Iswanto , Eva Vaulina Yulistia Delsi *1 , Ely Setiawan 1 1 and Heny Ekowati 2 ABSTRACT Background: Insecticides are substances used to control, repel, or eradicate troublesome organisms, particularly insect-based plant pests. The discovery of new insecticide compounds fuels the ongoing development of insecticides. The integration of computational chemistry into the development of insecticidal chemicals was beneficial. Objective: This study aims to identify the most suitable method among 12 available semiempirical calculation methods in the Hyperchem application. Methods: The selection process involved comparing experimental data of the infra-red spectrum of chlorpyrifos with corresponding calculation data. Results: The largest Predicted Residual of Sum Squares (PRESS) value was observed in the INDO method of 55466.3856. Conversely, the smallest PRESS value was observed in the AM1, measuring 3242.6549. The AM1 semiempirical method yields the smallest value. Conclusion: The results indicated that the calculation method chosen was the AM1 semiempirical method. Introduction Insecticides play a significant role in increasing agricultural production, particularly in controlling plant pests. However, insecticides also possess toxic properties. In Indonesia, most insecticides utilized belong to the organophosphate group, with chlorpyrifos being one example [1]. Chlorpyrifos is a highly toxic compound with an LC50 value of 0.024 g/L in fish [2]. This value is used to determine the toxicity of insecticides in a given concentration and its potential to cause the death of test animals [3,4]. Due to the various functional groups present, the use of insecticide combinations offers a variety of reaction mechanisms [5]. Laboratory of Physical Chemistry, Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Jenderal Soedirman, Jl. Dr. Soeparno, Karangwangkal, Purwokerto 53123, Indonesia 1 Laboratory of Pharmacology and Clinical Pharmacy, Department of Pharmacy, Faculty of Health Sciences, Universitas Jenderal Soedirman, Purwokerto, 53123 Indonesia 2 *Corresponding author: Jl. Dr. Soeparno Karangwangkal, Purwokerto 53123, Indonesia. E-mail: In the 1950s, the development of computer technology started molecular modeling. Techniques invented by artificial intelligence (AI) developing computational scientists have been mainly applied to drug design in recent years. These methods are called de novo or rational drug design [6]. The general method is used to identify the active functional group and enter the desired functional group to interact with other functional groups. This method also studies toxicological and anti-inflammatory effects [7]. Some researchers studied a compound, namely chlorpyrifos. Chlorpyrifos is a white solid with a sharp odor. If chlorpyrifos enters the body waters, it will kill aquatic biotas such as fish and shrimp. This chlorpyrifos insecticide is non-systemic and works when it comes in contact with the skin, is ingested, and is inhaled [8]. Its molecular formula is C9H11Cl3NO3PS, with a molecular weight of 350.59 g/mol. Chlorpyrifos has a melting point of 42 °C and a specific gravity of 1.4 g/cm³. It belongs to the organothiophosphate group, as illustrated in Figure 1. Copyright © The Author(s) 2023. This article is distributed under a Creative Commons Attribution 4.0 International License 1 Iswanto et al (2023) Selection of semi-empirical calculation methods for insecticide development Figure 1. Chlorpyrifos: an example of the organo-thiophosphate compound The present study employed a semi-empirical calculation method, which was carried out using the Hyperchem software. There are 12 different semiempirical methods available for calculation [9], and the method selected for chlorpyrifos calculation was based on experimental infrared (IR) spectra data [10,11]. Semiempirical methods utilize the principles of quantum mechanics [12], and the available methods in the software include Extended Huckel, Complete Neglect of Differential Overlap (CNDO), Intermediate Neglect of Differential Overlap (INDO), Modified Intermediate Neglect of Differential Overlap 3 (MINDO3), Modified Neglect of Diatomic Overlap (MNDO), Modified Neglect of Diatomic Overlap d (MNDOd), Austin Model 1 (AM1), Recife Model 1 (RM1), Parameterized Model 3 (PM3), Zero Intermediate Neglect of Differential Overlap-1 (ZINDO-1), Zero Intermediate Neglect of Differential Overlap-S (ZINDO-S), and Typed Neglect of Differential Overlap (TNDO) (HyperCube, 2007). The choice of the method was determined by comparing the results with the experimental IR spectra [11]. This study aims to select one method of 12 semi-empirical calculation methods available in the Hyperchem application. Methods Equipment This study was theoretical research conducted on a computer with the following specifications: Intel(R) Core (TM) i5-6500 CPU @ 3.20GHz, 8.00 GB RAM, Windows 10 64-bit operating system, x64 processor, and Hyperchem 8.0 Program. The research used the molecular model of chlorpyrifos and selected the semiempirical method based on the infrared spectrum (IR) obtained from previous studies [4]. Molecular modeling of chlorpyrifos After the chlorpyrifos molecule reached stable energy, the infrared spectrum was calculated using the Hyperchem Program. The calculation was performed Acta Pharmaciae Indonesia: Acta Pharm Indo 11(1): 7046 https://doi.org/10.20844/1.api.2023.11.1.7046 Figure 2. Geometry optimization of chlorpyrifos compound through semiempirical methods by selecting the Compute menu and the vibrational spectrum in the available options. Geometry optimization The chlorpyrifos molecule was drawn into a threedimensional (3D) shape, and the geometry optimization calculation was performed. The methods used for the calculation were the Extended Huckel method, AM1, CNDO, INDO, MINDO3, MNDO/d, MNDO, PM3, RM1, TNDO, ZINDO/1, and ZINDO/S, and the geometry optimization was set with parameters of RMS gradient = 0.01 kcal/(Å.mol), algorithm = Polak-Ribiere, molecular charge = 0 and spin multiplicity = 1. Infrared spectrum analysis The infrared spectrum was calculated using the Hyperchem Program by selecting the Compute menu and the vibrational spectrum from the available options. Method selection and analysis The data were obtained from the IR spectrum calculation method for each method used. The best calculation method was determined by the Predicted Residual of Sum Squares (PRESS) method, where the smallest value was chosen as the result. Results A molecular of chlorpyrifos was generated, then the model was transformed into a three-dimensional (3D) image and subjected to geometry optimization (Table 1). Subsequent to (...truncated)