Introduction

Quantum chemistry allows for the study of systems with chemical precision (1 kcal/mol from experiment), but it is limited to a few atoms due to computing costs. This has resulted in a continuing need to improve and simplify these procedures while maintaining accuracy. One way the area is optimising performance is by using Quantum Mechanical (QM) approaches on current technology such as multiple-Graphics Processing Units (GPU). Multiscale techniques, such as the so-called QM/molecular mechanical method, are gaining favour in drug development because they focus the application of QM methods to the region of interest (e.g., the binding site), while representing less important portions with efficient MM models. Another example is the development of simpler QM approaches, such as the use of machine learning to produce ultra-fast and accurate QM models. The application of QM in Computer-Aided Drug Design (CADD) has evolved over the last few decades. Due to the computational expense, the early focus on Quantum Mechanics (QM) was on tiny molecules, but with a variety of algorithmic and computer hardware improvements, the potential to genuinely employ QM in CADD has arisen. We will review key advancements in the last several years in what follows, but anyone interested in delving deeper into the area might study a recent book on QM in Drug Discovery, This gives a solid introduction of the area with contributed chapters covering QM techniques, protocols, and applications. In this section, we will look at recent advances in QM methods, hybrid QM/MM approaches, and newly developing Quantum Machine Learning (QML) methods that are relevant to CADD. QM approaches have a long history in CADD projects and continue to have an influence in the form of QM-based tools and workflows, as well as unique computational implementations of classic Quantum Chemical (QC) procedures. Their most current approach, GFN2-xTB, has gained popularity due to its application across the periodic table, excellent accuracy, and cheap computing cost. It is based on an updated version of tight binding and the D4 dispersion correction. Meanwhile, classic semi-empirical techniques, Hartree-Fock (HF), and Density Functional Theory (DFT) methods with better exchange correlation functionals remain effective in many disciplines of CADD, and approaches based on very accurate correlated wave function methods are emerging. Benchmark datasets of 547 Protein Fragment interaction energies (PLF547) and 15 active site-ligand models (PLA15) were created and used to evaluate the accuracy of several semi-empirical QM methods, demonstrating that when combined with noncovalent dispersion and hydrogen bonding corrections, PM6 and DFTB3 can achieve results comparable to dispersion corrected DFT. The linear scaling domain-based local pair natural orbital linked cluster is an example of a cutting-edge ab initio approach. A local energy decomposition analysis was used to measure ligand-residue interactions in nicotinic acetylcholine receptor agonist binding using the DLPNO-CCSD(T) approach. The ReSCoSS method for creating conformers of drug like compounds in solution has been disclosed in the field of conformer creation. The initial conformer generation in this semiautomated procedure is done using traditional methods, however the subsequent ranking of conformers based on relative free energies is done utilising geometry optimizations using the DFT-D method with the COSMO-RS solvent model. Meanwhile, Grimme's group has reported on the CREST tool, in which conformational space sampling is conducted iteratively and the following energy computation is performed using the GFN2-xTB approach. This method has been demonstrated to produce decent conformers with enough precision at a minimal computational cost. An analogous software technique for producing torsional conformers of tiny acyclic molecules has been developed. The torsional space is explored using chemical knowledge and a random search, and geometry optimizations and Hessian calculations are performed at both a low (HF/3-21G) and high (M08HX/MG3S) degree of theory.

High-throughput docking is one of the most extensively utilised approaches in drug lead development, with the ability to triage promising therapeutic candidates considerably quicker and more affordably than experimental methods. More recently, using absolute ligand binding energies, comprehensive DFT calculations were used to successfully rank order a scaffold-diverse collection of ligands to a SARS-CoV-2 Major protease (Mpro) model with over 3000 atoms. DFT calculations for such big models are substantially more expensive than semi-empirical scoring functions; yet, our study shows that more rigorous and large-scale QM techniques with manageable turnaround times may be used in the drug development pipeline. The former, which only considers carboxylic acids, is based on a linear connection between estimated atomic charges of anionic carboxylic fragments and experimental charges. The pKa values. Grimme's procedure, on the other hand, is a generally applicable protocol based on a novel cubic free energy relationship equation. MOSS-DFT for organic molecules in solution and the MIM2-NMR process for big biomolecules have been presented in the field of C13 and proton NMR spectra prediction.

Conclusion

A novel hybrid density functional for predicting C13 chemical shifts has also been developed. This xOPBE functional was created by combining HF exchange with the previously described OPBE functional. According to the authors, the anticipated C13 chemical shifts utilising this functional are more accurate than those using its parent functional. QM has been an important field in theoretical and computational chemistry for decades and will continue to be so in the future since it is the only one that exists. The variational principle is a strategy accessible in the computational arsenal that assures to asymptotically get the correct solution. However, improving the performance of classic QM approaches by utilising contemporary technology and innovative algorithms remains a subject of interest. New QM/MM approaches that take advantage of improvements are already beginning to appear in CADD applications. The ML/AI area is quickly expanding to give the CADD field with fast and accurate potentials that directly imitate QM models and can be used to a wide range of CADD challenges. The most interesting part of the application of QM in CADD has been the introduction of several new paths, all of which promise to bring chemical precision to various aspects of CADD in the next years.