notebooks/ligand_based/dhfr/dhfr.ipynb

{
 "cells": [
  {
   "cell_type": "markdown",
   "id": "faf1e736-b267-4f1e-bfdd-091c597d976c",
   "metadata": {},
   "source": [
    "# Dihydrofolate reductase (DHFR) ligands for pharmacophore identification\n",
    "\n",
    "We explore DHFR ligands that will be used to create ligand-based pharmacophore models"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 1,
   "id": "ccc5d674-bc0a-493c-b835-c722f532c7ee",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "application/vnd.jupyter.widget-view+json": {
       "model_id": "3b9ab513c2634249b3786246e2749506",
       "version_major": 2,
       "version_minor": 0
      },
      "text/plain": []
     },
     "metadata": {},
     "output_type": "display_data"
    }
   ],
   "source": [
    "import openpharmacophore as oph\n",
    "\n",
    "import pandas as pd\n",
    "import nglview as nv\n",
    "from rdkit import Chem\n",
    "from rdkit.Chem import Draw\n",
    "\n",
    "import os\n",
    "from pprint import pprint\n",
    "from IPython.display import SVG"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "ed3c0279-311c-459f-9ef9-958a61ed00c6",
   "metadata": {},
   "source": [
    "## Load  and visualize ligands\n",
    "\n",
    "We load the ligands from their respective smiles and draw their molecular structures"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 2,
   "id": "b7b21a74-7ec9-42e9-ba3a-f838615bab59",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/html": [
       "<div>\n",
       "<style scoped>\n",
       "    .dataframe tbody tr th:only-of-type {\n",
       "        vertical-align: middle;\n",
       "    }\n",
       "\n",
       "    .dataframe tbody tr th {\n",
       "        vertical-align: top;\n",
       "    }\n",
       "\n",
       "    .dataframe thead th {\n",
       "        text-align: right;\n",
       "    }\n",
       "</style>\n",
       "<table border=\"1\" class=\"dataframe\">\n",
       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th></th>\n",
       "      <th>Smiles</th>\n",
       "      <th>PDBID</th>\n",
       "      <th>LigID</th>\n",
       "    </tr>\n",
       "  </thead>\n",
       "  <tbody>\n",
       "    <tr>\n",
       "      <th>0</th>\n",
       "      <td>c1ccc(c(c1)C(=O)NCCC[C@@H](C(=O)O)NC(=O)c2ccc(...</td>\n",
       "      <td>1OHK</td>\n",
       "      <td>COP</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>1</th>\n",
       "      <td>c1cc(ccc1C(=O)N[C@@H](CCC(=O)O)C(=O)O)NCc2cnc3...</td>\n",
       "      <td>1DRF</td>\n",
       "      <td>FOL</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>2</th>\n",
       "      <td>c1cc(ccc1C(=O)N[C@@H](CCC(=O)O)C(=O)O)NCc2cc3c...</td>\n",
       "      <td>2DHF</td>\n",
       "      <td>DZF</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>3</th>\n",
       "      <td>C[N@](Cc1coc2c1c(nc(n2)N)N)c3ccc(cc3)C(=O)N[C@...</td>\n",
       "      <td>1HFP</td>\n",
       "      <td>MOT</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>4</th>\n",
       "      <td>C[N@](Cc1cc(ccc1OC)OC)c2cc3c(nc(nc3nc2)N)N</td>\n",
       "      <td>1BOZ</td>\n",
       "      <td>PRD</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>5</th>\n",
       "      <td>Cc1c(cnc2c1c(nc(n2)N)N)Cc3cc(ccc3OC)OC</td>\n",
       "      <td>1DLR</td>\n",
       "      <td>MXA</td>\n",
       "    </tr>\n",
       "  </tbody>\n",
       "</table>\n",
       "</div>"
      ],
      "text/plain": [
       "                                              Smiles PDBID LigID\n",
       "0  c1ccc(c(c1)C(=O)NCCC[C@@H](C(=O)O)NC(=O)c2ccc(...  1OHK   COP\n",
       "1  c1cc(ccc1C(=O)N[C@@H](CCC(=O)O)C(=O)O)NCc2cnc3...  1DRF   FOL\n",
       "2  c1cc(ccc1C(=O)N[C@@H](CCC(=O)O)C(=O)O)NCc2cc3c...  2DHF   DZF\n",
       "3  C[N@](Cc1coc2c1c(nc(n2)N)N)c3ccc(cc3)C(=O)N[C@...  1HFP   MOT\n",
       "4         C[N@](Cc1cc(ccc1OC)OC)c2cc3c(nc(nc3nc2)N)N  1BOZ   PRD\n",
       "5             Cc1c(cnc2c1c(nc(n2)N)N)Cc3cc(ccc3OC)OC  1DLR   MXA"
      ]
     },
     "execution_count": 2,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "lig_df = pd.read_csv(\"ligands.csv\")\n",
    "lig_df"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 3,
   "id": "09da8b05-e4dd-4841-a389-ef52996a8193",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "image/png": 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\n",
      "text/plain": [
       "<IPython.core.display.Image object>"
      ]
     },
     "execution_count": 3,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "ligands = [Chem.MolFromSmiles(smi) for smi in lig_df[\"Smiles\"]]\n",
    "legends = [l for l in lig_df[\"PDBID\"]]\n",
    "Draw.MolsToGridImage(ligands, legends=legends, molsPerRow=3)"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "2f063375-dcd7-4268-9818-825355d37c59",
   "metadata": {},
   "source": [
    "## Preparing the ligands\n",
    "\n",
    "We'll generate different conformers for each of the ligands and add hydrogens to them\n",
    "as well."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 4,
   "id": "9def1113-a144-4eb0-a190-1434ebf1d7ad",
   "metadata": {},
   "outputs": [],
   "source": [
    "# Add hydrogens\n",
    "pharmacophore = oph.LigandBasedPharmacophore()\n",
    "pharmacophore.ligands = ligands\n",
    "pharmacophore.add_hydrogens(ligands=\"all\")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 5,
   "id": "5509e578-db79-40b8-a547-e74d41eec5c1",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "[298, 140, 160, 177, 58, 16]\n"
     ]
    }
   ],
   "source": [
    "pharmacophore.generate_conformers(n_confs=-1, ligands=\"all\")\n",
    "print([l.GetNumConformers() for l in pharmacophore.ligands])"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "11232eac-37b5-4aa6-b266-11817379f13b",
   "metadata": {},
   "source": [
    "## View 3D structures"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 6,
   "id": "b4940202-35e1-4693-af93-854e4a31301e",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "application/vnd.jupyter.widget-view+json": {
       "model_id": "95dbbbec204b416bb4f20d176881e3a1",
       "version_major": 2,
       "version_minor": 0
      },
      "text/plain": [
       "NGLWidget()"
      ]
     },
     "metadata": {},
     "output_type": "display_data"
    }
   ],
   "source": [
    "lig_ind = 2\n",
    "conf_ind = 2\n",
    "nv.show_rdkit(pharmacophore.ligands[lig_ind], conf_ind=conf_ind)"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "21e76715-1b90-470d-9357-a3f68c9539c7",
   "metadata": {
    "tags": []
   },
   "source": [
    "## Chemical features\n",
    "\n",
    "We find chemical features in the ligands and visualize them."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 7,
   "id": "25c7558b-daed-4f54-b039-55bd5e978642",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "image/svg+xml": [
       "<svg baseProfile=\"full\" height=\"560px\" version=\"1.1\" viewBox=\"0 0 1200 560\" width=\"1200px\" xml:space=\"preserve\" xmlns=\"http://www.w3.org/2000/svg\" xmlns:rdkit=\"http://www.rdkit.org/xml\" xmlns:xlink=\"http://www.w3.org/1999/xlink\">\n",
       "<!-- END OF HEADER -->\n",
       "<rect height=\"560.0\" style=\"opacity:1.0;fill:#FFFFFF;stroke:none\" width=\"1200.0\" x=\"0.0\" y=\"0.0\"> </rect>\n",
       "<path class=\"bond-0 atom-0 atom-1\" d=\"M 29.6,105.8 L 32.4,90.8\" style=\"fill:none;fill-rule:evenodd;stroke:#FF7F7F;stroke-width:3.2px;stroke-linecap:butt;stroke-linejoin:miter;stroke-opacity:1\"/>\n",
       "<path class=\"bond-41 atom-0 atom-5\" d=\"M 29.6,105.8 L 41.3,115.6\" style=\"fill:none;fill-rule:evenodd;stroke:#FF7F7F;stroke-width:3.2px;stroke-linecap:butt;stroke-linejoin:miter;stroke-opacity:1\"/>\n",
       "<path class=\"bond-1 atom-1 atom-2\" d=\"M 32.4,90.8 L 46.7,85.7\" style=\"fill:none;fill-rule:evenodd;stroke:#FF7F7F;stroke-width:3.2px;stroke-linecap:butt;stroke-linejoin:miter;stroke-opacity:1\"/>\n",
       "<path class=\"bond-2 atom-2 atom-3\" d=\"M 46.7,85.7 L 58.3,95.5\" style=\"fill:none;fill-rule:evenodd;stroke:#FF7F7F;stroke-width:3.2px;stroke-linecap:butt;stroke-linejoin:miter;stroke-opacity:1\"/>\n",
       "<path class=\"bond-3 atom-3 atom-4\" d=\"M 58.3,95.5 L 55.6,110.5\" style=\"fill:none;fill-rule:evenodd;stroke:#FF7F7F;stroke-width:3.2px;stroke-linecap:butt;stroke-linejoin:miter;stroke-opacity:1\"/>\n",
       "<path class=\"bond-38 atom-3 atom-39\" d=\"M 58.3,95.5 L 72.6,90.4\" style=\"fill:none;fill-rule:evenodd;stroke:#FF7F7F;stroke-width:3.2px;stroke-linecap:butt;stroke-linejoin:miter;stroke-opacity:1\"/>\n",
       "<path class=\"bond-4 atom-4 atom-5\" d=\"M 55.6,110.5 L 41.3,115.6\" style=\"fill:none;fill-rule:evenodd;stroke:#FF7F7F;stroke-width:3.2px;stroke-linecap:butt;stroke-linejoin:miter;stroke-opacity:1\"/>\n",
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       "<path class=\"atom-38\" d=\"M 442.5 451.4 L 443.0 451.4 L 443.0 453.2 L 445.2 453.2 L 445.2 451.4 L 445.8 451.4 L 445.8 455.7 L 445.2 455.7 L 445.2 453.7 L 443.0 453.7 L 443.0 455.7 L 442.5 455.7 L 442.5 451.4 \" fill=\"#000000\"/>\n",
       "<path class=\"atom-39\" d=\"M 413.3 442.7 L 413.9 442.7 L 413.9 444.5 L 416.1 444.5 L 416.1 442.7 L 416.6 442.7 L 416.6 447.0 L 416.1 447.0 L 416.1 445.0 L 413.9 445.0 L 413.9 447.0 L 413.3 447.0 L 413.3 442.7 \" fill=\"#000000\"/>\n",
       "<path class=\"atom-40\" d=\"M 360.8 395.2 L 361.3 395.2 L 361.3 397.1 L 363.5 397.1 L 363.5 395.2 L 364.1 395.2 L 364.1 399.6 L 363.5 399.6 L 363.5 397.6 L 361.3 397.6 L 361.3 399.6 L 360.8 399.6 L 360.8 395.2 \" fill=\"#000000\"/>\n",
       "<path class=\"atom-41\" d=\"M 372.0 376.9 L 372.6 376.9 L 372.6 378.7 L 374.8 378.7 L 374.8 376.9 L 375.4 376.9 L 375.4 381.2 L 374.8 381.2 L 374.8 379.2 L 372.6 379.2 L 372.6 381.2 L 372.0 381.2 L 372.0 376.9 \" fill=\"#000000\"/>\n",
       "<path class=\"atom-42\" d=\"M 379.1 406.5 L 379.7 406.5 L 379.7 408.4 L 381.9 408.4 L 381.9 406.5 L 382.5 406.5 L 382.5 410.8 L 381.9 410.8 L 381.9 408.8 L 379.7 408.8 L 379.7 410.8 L 379.1 410.8 L 379.1 406.5 \" fill=\"#000000\"/>\n",
       "</svg>"
      ],
      "text/plain": [
       "<IPython.core.display.SVG object>"
      ]
     },
     "execution_count": 7,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "pharmacophore.find_chem_feats()\n",
    "drawing = pharmacophore.draw((300, 280))\n",
    "SVG(drawing.GetDrawingText())"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "ff00ef8e-0ecc-4d3a-8b5e-2a2e7a33b7d6",
   "metadata": {},
   "source": [
    "## Extracting common pharmacophores\n",
    "\n",
    "We extract common pharmacophores via recursive distance partitioning algorithm"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "3ecc2283-b2d0-4289-a0ff-05243531ea07",
   "metadata": {
    "tags": []
   },
   "source": [
    "### Finding 5-Point Pharmacophores"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 10,
   "id": "69610b9c-02ca-44d3-8bf9-a8e3c8204a11",
   "metadata": {},
   "outputs": [],
   "source": [
    "min_actives = len(pharmacophore.ligands) - 1\n",
    "n_points = 5"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 11,
   "id": "39790d51-cd5d-4bd4-b732-96868d73ef37",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Found 6 common pharmacophores\n"
     ]
    }
   ],
   "source": [
    "pharmacophore.extract(\n",
    "    n_points=n_points, min_actives=min_actives, max_pharmacophores=10\n",
    ")\n",
    "print(f\"Found {len(pharmacophore)} common pharmacophores\")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 12,
   "id": "eed27325-4226-4321-9a6b-9d30cca4c53c",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "application/vnd.jupyter.widget-view+json": {
       "model_id": "4672f367b0a44cd689fefb533bf94f08",
       "version_major": 2,
       "version_minor": 0
      },
      "text/plain": [
       "NGLWidget()"
      ]
     },
     "metadata": {},
     "output_type": "display_data"
    }
   ],
   "source": [
    "pharmacophore.show(0)"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "9ccadc53-bdf7-4c44-a0ec-7bfb2816f1a1",
   "metadata": {},
   "source": [
    "### Finding 4-Point Pharmacophores"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 13,
   "id": "8188afd9-5093-441c-99e2-4d6bb49f082c",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Found 10 common pharmacophores\n"
     ]
    }
   ],
   "source": [
    "min_actives = len(pharmacophore.ligands)\n",
    "n_points = 4\n",
    "\n",
    "pharma_4 = oph.LigandBasedPharmacophore()\n",
    "pharma_4.ligands = pharmacophore.ligands\n",
    "pharma_4.find_chem_feats()\n",
    "pharma_4.extract(\n",
    "    n_points=n_points, min_actives=min_actives, max_pharmacophores=10\n",
    ")\n",
    "\n",
    "print(f\"Found {len(pharma_4)} common pharmacophores\")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 14,
   "id": "94fa0a96-037e-44cf-8c84-c75a98e96493",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "application/vnd.jupyter.widget-view+json": {
       "model_id": "a5288949940b47f290f489828d95100c",
       "version_major": 2,
       "version_minor": 0
      },
      "text/plain": [
       "NGLWidget()"
      ]
     },
     "metadata": {},
     "output_type": "display_data"
    }
   ],
   "source": [
    "pharma_4.show()"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "bedcd7d9-0175-4bfa-b905-fe5e00268e2c",
   "metadata": {},
   "source": [
    "### Finding 3-Point Pharmacophores"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 16,
   "id": "3f05027b-4992-4204-a98b-383cc9b50017",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Found 10 common pharmacophores\n"
     ]
    }
   ],
   "source": [
    "min_actives = len(pharmacophore.ligands)\n",
    "n_points = 3\n",
    "\n",
    "pharma_3 = oph.LigandBasedPharmacophore()\n",
    "pharma_3.ligands = pharmacophore.ligands\n",
    "pharma_3.find_chem_feats()\n",
    "pharma_3.extract(\n",
    "    n_points=n_points, min_actives=min_actives, max_pharmacophores=10\n",
    ")\n",
    "\n",
    "print(f\"Found {len(pharma_3)} common pharmacophores\")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 17,
   "id": "9489bfc3-51ab-4f1e-9683-79c5b63aa32e",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "application/vnd.jupyter.widget-view+json": {
       "model_id": "cb203ae0583b4d1c90d6f94170459eff",
       "version_major": 2,
       "version_minor": 0
      },
      "text/plain": [
       "NGLWidget()"
      ]
     },
     "metadata": {},
     "output_type": "display_data"
    }
   ],
   "source": [
    "pharma_3.show(0)"
   ]
  }
 ],
 "metadata": {
  "kernelspec": {
   "display_name": "Python 3 (ipykernel)",
   "language": "python",
   "name": "python3"
  },
  "language_info": {
   "codemirror_mode": {
    "name": "ipython",
    "version": 3
   },
   "file_extension": ".py",
   "mimetype": "text/x-python",
   "name": "python",
   "nbconvert_exporter": "python",
   "pygments_lexer": "ipython3",
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